Pyrimidine-2,4-diamine derivatives for treatment of cancer

ABSTRACT

A compound of formula I, 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically-acceptable salt thereof. The compound is useful in the treatment of cancer or other diseases that may benefit from inhibition of MTH1.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/647,400, filed on May 26, 2015, which is a U.S. National StageApplication under 35 U.S.C. §371 of International Application No.PCT/SE2013/051387, filed on Nov. 26, 2013, which claims the benefit ofU.S. Provisional Application No. 61/797,022, filed on Nov. 27, 2012, andSwedish Application No. 1251332-1, filed on Nov. 27, 2012, the entiredisclosures of which are hereby incorporated by reference for any andall purposes.

FIELD OF THE INVENTION

The invention relates to novel compounds, compositions and methods fortreatment of cancer. In particular, the invention relates to novelcompounds, compositions and methods for the treatment of cancers throughinhibition of MTH1.

BACKGROUND OF THE INVENTION

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

BACKGROUND

Dysfunctional redox regulation of cellular signalling and an increasedROS (Reactive oxygen species) tension have been demonstrated to play acrucial role in cancer etiology, progression and metastasis (Zhang etal., Antioxid Redox Signal 15(11)2011:2876-2908). ROS mediatestumor-promoting characteristics, such as e.g. unrestrainedproliferation, survival signaling, increased migration, angiogenesis.ROS are generated during cell metabolism and are highly reactive withmacromolecules such as DNA, proteins and lipids. Exposure of nucleicacids to ROS can create more than 20 oxidatively modified nucleotides,of which 8-oxo-7,8-dihydroxyguanine (8-oxo-dG) is most abundant.8-oxo-dG plays a pivotal role in mutagenesis (Sekiguchi and Tsuzuki,Oncogene 21(58)2002:8895-906). To protect themselves from carcinogeniceffects, mammalian cells are armed with a set of repair enzymes toremove the oxidized nucleotides to maintain genome integrity. One ofthese protective enzymes is MTH1 (MutT homologue 1, 8-oxo-dGTPase,NUDT1). Interestingly, MTH1 is upregulated in various cancer forms,suggesting that the cancer cell rely on MTH1 function to survive theincreased DNA lesion (Human Proteinatlas, Koketsu et al.,Hepatogastroenterology, 51(57)2004:638-41). Suppression of MTH1 leveland activity by using RNAi technology, leads to reduced cancer cellsurvival, premature senescence and DNA strand breaks (Rai et al, PNAS,106(1)2009:169-174), Helleday et al unpublished data). Interestingly,lung cancers which spontaneously form in OGG−/− mice are prevented fromforming in crosses with the MTH1−/− mice, suggesting that MTH1 isrequired for lung cancer cells to survive (Sakumi et al., Cancer Res 63,2003: 902). We have observed that downregulation of MTH1 protein levelsin human colon cancer tumors in xenograft mice model reduced tumorgrowth and significantly shrinked the tumour (Helleday et al,unpublished data).

In tumour cells, reducing the capacity to eliminate oxidised dNTPs byinhibiting MTH1 activity, will reduce cancer cell survival and hence bea promising novel anticancer therapy, either as monotherapy in cancerforms with high oxidative stress levels and/or in combination withradiotherapy and chemotherapy drugs.

Shortcomings and Complications with Current Treatment

Today's treatment of cancer is not effective for all patients withdiagnosed disease also including a large proportion of patients thatexperience adverse effects from treatments with existing therapies orwhere resistance to on-going therapy is developed over time.

PRIOR ART

Engelhardt, H. et al. Journal of Medicinal Chemistry (2013), 56(11),4264-4276 and US patent application US 2010/0016344 disclose certain6-aryl-2,4-diaminopyrimidines having an additional pyrimidine appendageas histamine H4 receptor modulators. The compounds are claimed to beuseful for a various diseases including cancer pain, but their use inthe treatment of cancer as such is neither disclosed or suggested.

International patent application WO 2013/066839 discloses6-(3-pyridyl)-(2,4-diaminopyrimidines as HDAC inhibitors. However, thesubstituent on the 4-amino group contains a prerequisite5-trifluoromethyl-1,2,4-oxadiazol-3-yl group. 2,4-Diaminopyrimidinessubstituted in the 6-position with 3-aminoindazoles have been describedin international patent application WO 2010/059658. Although alsoindazoles without the amino groups are mentioned, it is evident from theexamples that the 3-amino substituent on the indazole is required foractivity. The same document also describes 2,4-diaminopyrimidinessubstituted in the 6-position by a 3-cyano-2-fluorophenyl group.However, these compounds are merely precursors to the 3-aminoindazolesmentioned above and there is no disclosure or suggestions in thedocument that they possess any anti-cancer activity.

International patent application WO 2006/078886 describes2,4-diaminopyrimidines substituted in the 6-position by an aryl group aswnt modulators. The 4-aryl group is lacking any substituents or must besubstituted in the 3-position by methoxy. The document does not discloseor suggest compounds with any other substituent-pattern, nor does itmention or suggest the use of such compounds in the treatment of cancer.Moreover, in all examples the 4-amino group of the pyrimidine issubstituted by either 1,3-benzodioxol-5-ylmethyl or by4-hydroxy-phenethyl. Several scientific publications describe the use ofone of the compounds(N4-(1,3-benzodioxol-5-ylmethyl)-6-(3-methoxyphenyl)-2,4-pyrimidinediamine)as a tool to investigate the wnt-pathway.

International patent application WO 86/04583 describes aziridinylsubstituted anti-neoplastic compounds. There is only one compound thathas both a 6-aryl substituent and a 4-N-alkyl group attached to2-aminopyrimidine core. The compound has besides the aziridinyl group afluorine in the 5-position of the pyrimidine ring. Both the aziridinyland the fluorine are implied to be important for the activity and thereis nothing that suggests that anti-neoplastic activity can be obtainedwithout at least one of these substituents.

British patent application GB 681712 describes 2,4-diaminopyrimidinessubstituted in the 6-position by an aryl group for use in the treatmentof cancer, but in only one example the aryl is phenyl and the 4-aminogroup is substituted by an alkyl. In this compound the phenyl isunsubstituted and the alkyl is methyl.

There is no disclosure in this documents of compounds in which the6-phenyl may be substituted by other groups than chloro or nitro in thepara-position, that the 6-phenyl may contain more than one substituentor that the 4-alkylamino-group is larger than methyl or may carrysubstituents.

Two publications from the group of H. Junjappa (Indian Journal Chemistry(1985), 24B 466; Synthesis (1980), 748) describe the synthesis ofcertain 2-amino-4-(N-alkylamino)-6-arylpyrimidines. The publications donot mention or suggest the use of the synthesized compounds in thetreatment of cancer.

There are numerous 2-amino-4-(N-alkylamino)-6-arylpyrimidines that are,or that at some point have been stated to be, commercially available butthat do not have any ascribed pharmaceutical use, nor any other use,ascribed to them.

MTH1 inhibitors have been described in Streib, M. et al. AngewandteChemie, Int., Ed. (2013), Vol. 52. The compounds are organometallic andare not 2-amino-4-(N-alkylamino)-6-aryl pyrimidines.

SUMMARY OF THE INVENTION

Although the finding of oncogenes and development of new anticancertreatments and diagnosis have improved the life length of cancerpatients, there is still a high medical need to find more effective andless toxic treatments for e.g. breast cancer, leukemia, colon or lungcancer. Our preliminary data suggests that MTH1 inhibitors have thepotential to be very effective against cancer forms with dysfunctionalredox status, with minimal general toxic effects. MTH1 inhibition mayalso be a suitable adjuvant therapy to be used in conjunction withradiotherapies or other chemotherapeutic approaches.

The present invention aims at providing new treatments for cancer thatcan be achieved by inhibition of MTH1

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Effect on cell survival following MTH1 siRNA depletion invarious human cancer and normal cell lines.

FIG. 2. MTH1 inhibitor reduce cell survival in various cancer celllines, with less effect on normal immortalised cells (VH10 and BJ hTERT)

DETAILED DESCRIPTION OF THE INVENTION

There is provided a compound of formula I,

for use in the treatment of cancerwherein:R¹ represents heteroaryl connected to the pyrimidine of formula I via acarbon atom of the heteroaryl ring, which heteroaryl ring is optionallysubstituted by one or more substituents selected from Y¹, —C₁₋₆alkyloptionally substituted by one or more Y² and heterocycloalkyl optionallysubstituted by one or more Y³; or aryl represented by

E¹ represents hydrogen, Y^(1a), —C₁₋₆alkyl optionally substituted by oneor more Y² or heterocycloalkyl optionally substituted by one or more Y³;E² represents hydrogen, Y^(1b), —C₁₋₆alkyl optionally substituted by oneor more Y² or heterocycloalkyl optionally substituted by one or more Y³;E³ and E⁴ each independently represents hydrogen, Y¹, —C₁₋₆alkyloptionally substituted by one or more Y² or heterocycloalkyl optionallysubstituted by one or more Y³;R² represents hydrogen, halogen, —CN, —C₁₋₁₂alkyl optionally substitutedby one or more Z¹, or heterocycloalkyl optionally substituted by one ormore Z²;R³ represents —C₁₋₁₂alkyl optionally substituted by one or more Z¹ orheterocycloalkyl optionally substituted by one or more Z²; orR² and R³ are linked together to form, along with the atoms to whichthey are attached, a 5- to 8-membered non-aromatic ring, wherein thelink formed by R² and R³ is optionally substituted by one or moresubstituents selected from Z³ and —C₁₋₉alkyl optionally substituted byone or more Z⁴;each Y¹ independently represents halogen, —CN, —C(O)R^(a),—C(O)N(R^(b))R^(c), —C(O)OR^(d), —N(R^(e))R^(f), —N(R^(g))C(O)R^(h),—N(R^(i))C(O)OR^(j), —N(R^(k))C(O)N(R^(l))R^(m), —NO₂,—N(R^(n))S(O)₂R^(o), —OR^(p), —OC(O)R^(q), —OS(O)₂R^(r), —S(O)_(m)R^(s),—S(O)₂N(R^(t))R^(u), heterocycloalkyl optionally substituted by one ormore substituents selected from W², aryl optionally substituted by oneor more substituents selected from W³ or heteroaryl optionallysubstituted by one or more substituents selected from W³;Y^(1a) represents halogen, —CN, —C(O)R^(a), —C(O)N(R^(b))R^(c),—C(O)OR^(d), —N(R^(e))R^(f), —N(R^(g))C(O)R^(h), —N(R^(i))C(O)OR^(j),—N(R^(k))C(O)N(R^(l))R^(m), —NO₂, —N(R^(n))S(O)₂R^(o), —OR^(py),—OC(O)R^(q), —OS(O)₂R^(r), —S(O)_(m)R^(s), —S(O)₂N(R^(t))R^(u),heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³ or heteroaryl optionally substituted byone or more substituents selected from W³;Y^(1b) represents halogen, —CN, —C(O)R^(a), —C(O)N(R^(b))R^(c),—C(O)OR^(d), —N(R^(e))R^(f), —N(R^(g))C(O)R^(h), —N(R^(i))C(O)OR^(j),—N(R^(k))C(O)N(R^(l))R^(m), —NO₂, —N(R^(n))S(O)₂R^(o), —OR^(py),—OC(O)R^(q), —OS(O)₂R^(r), —S(O)_(m)R^(s), —S(O)₂N(R^(t))R^(u),heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³ or heteroaryl optionally substituted byone or more substituents selected from W³;each R^(a), R^(b), R^(c), R^(d), R^(e), R^(g), R^(h), R^(i), R^(k),R^(l), R^(m), R^(n), R^(p), R^(q), R^(s), R^(t) and R^(u) independentlyrepresents hydrogen, —C₁₋₆ alkyl optionally substituted by one or moresubstituents selected from W¹, heterocycloalkyl optionally substitutedby one or more substituents selected from W², aryl optionallysubstituted by one or more substituents selected from W³, or heteroaryloptionally substituted by one or more substituents selected from W³; orany two R^(b) and R^(c), R^(e) and R^(f), R^(l) and R^(m) and/or R^(t)and R^(u) are linked together to form, along with the nitrogen atom towhich they are attached, a 3- to 8-membered monocyclic or bicyclic ring,which ring optionally contains one or two further heteroatoms and whichring optionally is substituted by one or more substituents selected fromW², C₁₋₃alkyl optionally substituted by one or more substituentsselected from W¹, and ═O;each R^(f), R^(j), R^(o), R^(r) and R^(px) independently represents C₁₋₆alkyl optionally substituted by one or more substituents selected fromW¹, heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³ or heteroaryl optionally substituted byone or more substituents selected from W³;R^(py) represents hydrogen, —C₂₋₆ alkyl optionally substituted by one ormore substituents selected from W¹, heterocycloalkyl optionallysubstituted by one or more substituents selected from W², aryloptionally substituted by one or more substituents selected from W³, orheteroaryl optionally substituted by one or more substituents selectedfrom W³;each Y² independently represents halogen, —CN, —C(O)R^(b1),—C(O)N(R^(c1))R^(d1), —C(O)OR^(e1), —N(R^(f1))R^(g1),—N(R^(h1))C(O)R^(i1), —N(R^(j1))C(O)OR^(k1),—N(R^(l1))C(O)N(R^(m1))R^(n1), —N(R^(o1))S(O)₂R^(p1), —OR^(q1),—OC(O)R^(r1), —OS(O)₂R^(s1), —S(O)_(m)R^(t1), —S(O)₂N(R^(u1))R^(v1),heterocycloalkyl optionally substituted by one or more substituentsselected from W¹, aryl optionally substituted by one or moresubstituents selected from W², heteroaryl optionally substituted by oneor more substituents selected from W², or ═O;each Y³ independently represents halogen, —R^(a1), —CN, —C(O)R^(b1),—C(O)N(R^(c1))R^(d1), —C(O)OR^(e1), —N(R^(f1))R^(g1),—N(R^(h1))C(O)R^(i1), —N(R^(j1))C(O)OR^(k1),—N(R^(l1))C(O)N(R^(m1))R^(n1), —N(R^(o1))S(O)₂R^(p1), —OR^(q1),—OC(O)R^(r1), —OS(O)₂R^(s1), —S(O)_(m)R^(t1), —S(O)₂N(R^(u1))R^(v1),heterocycloalkyl optionally substituted by one or more substituentsselected from W¹, aryl optionally substituted by one or moresubstituents selected from W², heteroaryl optionally substituted by oneor more substituents selected from W², or ═O;each R^(a1), R^(b1), R^(c1), R^(d1), R^(e1), R^(f1), R^(h1), R^(i1),R^(j1), R^(l1), R^(m1), R^(n1), R^(o1), R^(q1), R^(r1), R^(t1), R^(u1)and R^(v1) independently represents hydrogen, C₁₋₆ alkyl optionallysubstituted by one or more substituents selected from W¹,heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³, or heteroaryl optionally substituted byone or more substituents selected from W³; orany two R^(c1) and R^(d1), R^(f1) and R^(g1), R^(m1) and R^(n1) and/orR^(u1) and R^(v1) are linked together to form, along with the nitrogenatom to which they are attached, a 3- to 8-membered monocyclic orbicyclic ring, which ring optionally contains one or two heteroatoms andwhich ring optionally is substituted by one or more substituentsselected from W², C₁₋₃alkyl optionally substituted by one or moresubstituents selected from W¹, and ═O;each R^(g1), R^(k1), R^(p1) and R^(s1) independently represents —C₁₋₆alkyl optionally substituted by one or more substituents selected fromW¹, heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³, or heteroaryl optionally substituted byone or more substituents selected from W³;each Z¹ independently represents halogen, —CN, —C(O)R^(b2),—C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2),—N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl represented by

heteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or onesulfur atom and optionally substituted by one or more substituentsselected from W⁶, or ═O;each Z² and Z³ independently represents halogen, —R^(a2), —CN,—C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2),—N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶;each Z⁴ independently represents halogen, —CN, —C(O)R^(b2),—C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2),—N(R^(h2))C(O)R^(i2), N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, heteroaryl optionally substituted by oneor more substituents selected from W⁶, or ═O;each R^(a2), R^(b2), R^(c2), R^(d2), R^(e2), R^(f2), R^(h2), R^(i2),R^(j2), R^(l2), R^(m2), R^(n2), R^(o2), R^(r2), R^(t2), R^(u2) andR^(v2) independently represents hydrogen, C₁₋₆ alkyl optionallysubstituted by one or more substituents selected from W⁴,heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶; orany two R^(c2) and R^(d2), R^(f2) and R^(g2), R^(m2) and R^(n2) and/orR^(u2) and R^(v2) are linked together to form, along with the nitrogenatom to which they are attached, a 3- to 8-membered monocyclic orbicyclic ring, which ring optionally contains one or two heteroatoms andwhich ring optionally is substituted by one or more substituentsselected from W⁵, C₁₋₃alkyl optionally substituted by one or moresubstituents selected from W⁴), and ═O;each R^(g2), R^(k2), R^(p2), R^(q2) and R^(s2) independently representsC₁₋₆ alkyl optionally substituted by one or more substituents selectedfrom W⁴, heterocycloalkyl optionally substituted by one or moresubstituents selected from W⁵, aryl optionally substituted by one ormore substituents selected from W⁶, or heteroaryl optionally substitutedby one or more substituents selected from W⁶;each W¹ and W⁴ independently represents halogen, —CN, —N(R^(f3))R^(g3),—N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², heteroaryl optionally substituted by oneor more substituents selected from G², or ═O;each W², W³, W⁵ and W⁶ independently represents halogen, —R^(a3), —CN,—C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3),—N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², heteroaryl (optionally substituted by oneor more substituents selected from G², or ═O;each W⁷, W⁸, W¹⁰ and W¹¹ independently represents hydrogen, halogen,—R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3),—N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², or heteroaryl optionally substituted byone or more substituents selected from G²;W⁹ represents hydrogen, halogen, —R^(a3), —CN, —C(O)R^(b3),—C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3),—N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², or heteroaryl optionally substituted byone or more substituents selected from G²;each R^(a3), R^(b3), R^(c3), R^(d3), R^(e3), R^(f3), R^(h3), R^(i3),R^(j3), R^(l3), R^(m3), R^(n3), R^(o3), R^(q3), R^(r3), R^(t3), R^(u3)and R^(v3) independently represents hydrogen or C₁₋₆ alkyl optionallysubstituted by one or more G³; orany two R^(c3) and R^(d3), R^(f3) and R^(g3), R^(m3) and R^(n3) and/orR^(u3) and R^(v3) are linked together to form, along with the nitrogenatom to which they are attached, a 4- to 6-membered ring, which ringoptionally contains one heteroatom and which ring optionally issubstituted by one or more G²;each R^(g3), R^(k3), R^(p3), R^(q3) and R^(s3) independently representsC₁₋₆ alkyl optionally substituted by one or more G³;R^(q3x) represents C₂₋₆ alkyl optionally substituted by one or more G³;each G¹ and G² independently represents halogen, —R^(a4), —CN,—C(O)R^(b4), —C(O)N(R^(c4))R^(d4), —C(O)OR^(e4), —N(R^(f4))R^(g4),—N(R^(i4))C(O)R^(i4), —N(R^(j4))C(O)OR^(k4),—N(R^(l4))C(O)N(R^(m4))R^(n4), —N(R^(o4))S(O)₂R^(p4), —OR^(q4),—OC(O)R^(r4), —OS(O)₂R^(s4), —S(O)_(m)R^(t4), —S(O)₂N(R^(u4))R^(v4), or═O;G³ represents halogen, —CN, —C(O)R^(b4), —C(O)N(R^(c4))R^(d4),—C(O)OR^(e4), —N(R^(f4))R^(g4), —N(R^(h4))C(O)R^(i4),—N(R^(j4))C(O)OR^(k4), —N(R^(l4))C(O)N(R^(m4))R^(n4),—N(R^(o4))S(O)₂R^(p4), —OR^(q4), —OC(O)R^(r4), —OS(O)₂R^(s4),—S(O)_(m)R^(t4), —S(O)₂N(R^(u4))R^(v4), or ═O;each R^(a4), R^(b4), R^(c4), R^(d4), R^(e4), R^(f4), R^(h4), R^(i4),R^(j4), R^(l4), R^(m4), R^(n4), R^(o4), R^(q4), R^(r4), R^(t4), R^(u4)and R^(v4) independently represents hydrogen or C₁₋₆ alkyl optionallysubstituted by one or more —F; orany two R^(c4) and R^(d4), R^(f4) and R^(g4), R^(m4) and R^(n4) and/orR^(u4) and R^(v4) are linked together to form, along with the nitrogenatom to which they are attached, a 3- to 6-membered ring, which ringoptionally substituted by one or more —F, —CH₃, —CH₂CH₃, —CHF₂, —CF₃,—CH₂CF₃, or ═O;each R^(g4), R^(k4), R^(p4) and R^(s4) independently represent C₁₋₆alkyl optionally substituted by one or more —F;each m independently represents 0, 1 or 2;provided that formula I does not represent

-   6-(3-pyridinyl)-N⁴-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,4-pyrimidinediamine,-   6-(3-pyridinyl)-N⁴-[[5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2-pyridinyl]methyl]-2,4-pyrimidinediamine,-   6-(3-pyridinyl)-N⁴-[[5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2-pyrimidinyl]-methyl]-2,4-pyrimidinediamine    or-   N⁴-[2-(1-aziridinyl)ethyl]-5-fluoro-6-phenyl-2,4-pyrimidinediamine,    or a pharmaceutically acceptable salt thereof;    which compounds may be referred to herein as “the compounds of the    invention”.

Pharmaceutically-acceptable salts include acid addition salts and baseaddition salts. Such salts may be formed by conventional means, forexample by reaction of a free acid or a free base form of a compound offormula I with one or more equivalents of an appropriate acid or base,optionally in a solvent, or in a medium in which the salt is insoluble,followed by removal of said solvent, or said medium, using standardtechniques (e.g. in vacuo, by freeze-drying or by filtration). Salts mayalso be prepared by exchanging a counter-ion of a compound of theinvention in the form of a salt with another counter-ion, for exampleusing a suitable ion exchange resin. For the avoidance of doubt,solvates are also included within the scope of the invention.

Compounds of the invention may contain double bonds and may thus existas E (entgegen) and Z (zusammen) geometric isomers about each individualdouble bond. All such isomers and mixtures thereof are included withinthe scope of the invention.

Compounds of the invention may also exhibit tautomerism. All tautomericforms and mixtures thereof are included within the scope of theinvention.

Compounds of the invention may also contain one or more asymmetriccarbon atoms and may therefore exhibit optical and/ordiastereoisomerism. Diastereoisomers may be separated using conventionaltechniques, e.g. chromatography or fractional crystallisation. Thevarious stereoisomers may be isolated by separation of a racemic orother mixture of the compounds using conventional, e.g. fractionalcrystallisation or HPLC, techniques. Alternatively the desired opticalisomers may be made by reaction of the appropriate optically activestarting materials under conditions which will not cause racemisation orepimerisation (i.e. a ‘chiral pool’ method), by reaction of theappropriate starting material with a ‘chiral auxiliary’ which cansubsequently be removed at a suitable stage, by derivatisation (i.e. aresolution, including a dynamic resolution), for example with ahomochiral acid followed by separation of the diastereomeric derivativesby conventional means such as chromatography, or by reaction with anappropriate chiral reagent or chiral catalyst all under conditions knownto the skilled person. All stereoisomers and mixtures thereof areincluded within the scope of the invention.

Unless otherwise specified, C_(1-q) alkyl groups (where q is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number (i.e. a minimum of two or three, as appropriate)of carbon atoms, be branched-chain, and/or cyclic (so forming aC_(3-q)-cycloalkyl group). When there is a sufficient number (i.e. aminimum of four) of carbon atoms, such groups may also be part cyclic.Such alkyl groups may also be saturated or, when there is a sufficientnumber (i.e. a minimum of two) of carbon atoms, be unsaturated (forming,for example, a C_(2-q) alkenyl or a C_(2-q) alkynyl group).

Unless otherwise specified, C_(1-q) alkylene groups (where q is theupper limit of the range) defined herein may (in a similar manner to thedefinition of C_(1-q) alkyl) be straight-chain or, when there is asufficient number (i.e. a minimum of two or three, as appropriate) ofcarbon atoms, be branched-chain, and/or cyclic (so forming aC_(3-q)-cycloalkylene group). When there is a sufficient number (i.e. aminimum of four) of carbon atoms, such groups may also be part cyclic.Such alkylene groups may also be saturated or, when there is asufficient number (i.e. a minimum of two) of carbon atoms, beunsaturated (forming, for example, a C_(2-q)alkenylene or aC_(2-q)alkynylene group). Particular alkylene groups that may bementioned include those that are straight-chained and saturated.

The term “halo”, when used herein, includes fluoro, chloro, bromo andiodo (for example, fluoro and chloro).

Heterocycloalkyl groups that may be mentioned include non-aromaticmonocyclic and bicyclic heterocycloalkyl groups (which groups mayfurther be bridged) in which at least one (e.g. one to four) of theatoms in the ring system is other than carbon (i.e. a heteroatom), andin which the total number of atoms in the ring system is between threeand twelve (e.g. between five and ten and, most preferably, betweenthree and eight, e.g. a 5- or 6-membered heterocycloalkyl group).Further, such heterocycloalkyl groups may be saturated or unsaturatedcontaining one or more double and/or triple bonds, forming for example aC_(2-q) (e.g. heterocycloalkenyl (where q is the upper limit of therange) or a C_(7-q) heterocycloalkynyl group. C_(2-q) heterocycloalkylgroups that may be mentioned include 7-azabicyclo-[2.2.1]heptanyl,6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl,8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl,dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl),dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyland 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl(including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl,7-oxabicyclo-[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl, oxetanyl,oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl,pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl,3-sulfolenyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyridyl(such as 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl),thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including1,3,5-trithianyl), tropanyl and the like. Substituents onheterocycloalkyl groups may, where appropriate, be located on any atomin the ring system including a heteroatom. Further, in the case wherethe substituent is another cyclic compound, then the cyclic compound maybe attached through a single atom on the heterocycloalkyl group, forminga so-called “spiro”-compound. The point of attachment ofheterocycloalkyl groups may be via any atom in the ring system including(where appropriate) a heteroatom (such as a nitrogen atom), or an atomon any fused carbocyclic ring that may be present as part of the ringsystem. Heterocycloalkyl groups may also be in the N- or S-oxidisedform. At each occurrence when mentioned herein, a heterocycloalkyl groupis preferably a 3- to 8-membered heterocycloalkyl group (e.g. a 5- or6-membered heterocycloalkyl group).

The term “aryl”, when used herein, includes C₆₋₁₄ (e.g. C₆₋₁₀ aromaticgroups. Such groups may be monocyclic or bicyclic and, when bicyclic, beeither wholly or partly aromatic. C₆₋₁₀ aryl groups that may bementioned include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl,and the like (e.g. phenyl, naphthyl and the like). For the avoidance ofdoubt, the point of attachment of substituents on aryl groups may be viaany carbon atom of the ring system.

The term “heteroaryl” (or heteroaromatic), when used herein, includes 5-to 10-membered heteroaromatic groups containing one or more heteroatomsselected from oxygen, nitrogen and/or sulfur. Such heteroaryl group maycomprise one, or two rings, of which at least one is aromatic.Substituents on heteroaryl/heteroaromatic groups may, where appropriate,be located on any atom in the ring system including a heteroatom. Thepoint of attachment of heteroaryl/heteroaromatic groups may be via anyatom in the ring system including (where appropriate) a heteroatom.Bicyclic heteroaryl/heteroaromatic groups may comprise a benzene ringfused to one or more further aromatic or non-aromatic heterocyclicrings, in which instances, the point of attachment of the polycyclicheteroaryl/heteroaromatic group may be via any ring including thebenzene ring or the heteroaryl/heteroaromatic or heterocycloalkyl ring.Examples of heteroaryl/heteroaromatic groups that may be mentionedinclude pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl,thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, pyrimidinyl,indolyl, azaindolyl, pyrazinyl, indazolyl, pyrimidinyl, quinolinyl,isoquinolinyl, benzofuranyl, benzothiophenyl, benzoimidazolyl,benzoxazolyl, benzothiazolyl and benzotriazolyl. The oxides ofheteroaryl/heteroaromatic groups are also embraced within the scope ofthe invention (e.g. the N-oxide). As stated above, heteroaryl includespolycyclic (e.g. bicyclic) groups in which one ring is aromatic (and theother may or may not be aromatic). Hence, other heteroaryl groups thatmay be mentioned include e.g. benzo[1,3]dioxolyl, benzo[1,4]dioxinyl,indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl,1,2,3,4-tetra-hydroquinolinyl and the like.

Heteroatoms that may be mentioned include phosphorus, silicon, boronand, preferably, oxygen, nitrogen and sulfur.

For the avoidance of doubt, in cases in which the identity of two ormore substituents in a compound of the invention may be the same, theactual identities of the respective substituents are not in any wayinterdependent.

For the avoidance of doubt, when R¹ is defined as

it is connected to the rest of formula I by the bond interrupted by thewiggly line, and formula I can thus be represented by

Likewise, when R³ is —C₁₋₁₂ alkyl substituted by Z¹, and Z¹ isrepresented by

then, if e.g. R³ is C₂alkyl, then formula I can be represented by

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature (or the most abundant one found in nature). Allisotopes of any particular atom or element as specified herein arecontemplated within the scope of the compounds of the invention. Hence,the compounds of the invention also include deuterated compounds, i.e.in which one or more hydrogen atoms are replaced by the hydrogen isotopedeuterium.

All individual features (e.g. preferred features) mentioned herein maybe taken in isolation or in combination with any other feature(including preferred features) mentioned herein (hence, preferredfeatures may be taken in conjunction with other preferred features, orindependently of them).

The skilled person will appreciate that compounds of the invention thatare the subject of this invention include those that are stable. Thatis, compounds of the invention include those that are sufficientlyrobust to survive isolation from e.g. a reaction mixture to a usefuldegree of purity.

Particular compounds of formula I that may be mentioned include those inwhich:

R² represents hydrogen or —C₁₋₁₂alkyl optionally substituted by one ormore Z¹;andR³ represents —C₁₋₁₂alkyl optionally substituted by one or more Z¹ orheterocycloalkyl optionally substituted by one or more Z².

For example, compounds of formula I that may be mentioned include thosein which R² represents methyl, or preferably, hydrogen and R³represents:

-   (a) —C₁₋₁₂alkyl (for example —C₁₋₆alkyl) optionally substituted by    two, or preferably, one Z¹ or-   (b) —C₂₋₆alkyl optionally substituted by two, or preferably, one Z¹    or heterocycloalkyl optionally substituted by two, or preferably,    one Z²; or-   (c) —C₁₋₂alkyl optionally substituted with one or more —F; or-   (d)

-   (e) —C₁₋₁₂alkyl (for example —C₁₋₆alkyl) substituted by heteroaryl    having 1 to 3 nitrogen atoms, one oxygen atom and/or one sulfur atom    and which heteroaryl is optionally substituted by one or more    substituents selected from W³; or-   (f) a —C₃₋₆alkyl or a heterocycloalkyl selected from cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,    cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl,    cyclobutylethyl, cyclopropylpropyl, oxetanyl, tetrahydrofuryl,    tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl or morpholinyl wherein the C₃₋₆alkyl is optionally    substituted by two, or preferably, one Z¹ and the heterocycloalkyl    is optionally substituted by two, or preferably, one Z².

Particular compounds of formula I that may be mentioned include those inwhich: R² and R³ are linked together to form, along with the atoms towhich they are attached, a 5- to 8-membered non-aromatic ring, whereinthe link formed by R² and R³ is optionally substituted by one or moresubstituents selected from Z³ or —C₁₋₉alkyl optionally substituted byone or more Z⁴.

For example, compounds of formula I that may be mentioned include thosein which R² and R³ are linked together to form, along with the atoms towhich they are attached, a 5- to 6-membered non-aromatic ring, whereinthe non-aromatic ring is:

-   (a) unsubstituted; or-   (b) substituted by one or more substituents selected from Z³; or-   (c) substituted by —C₁₋₉alkyl optionally substituted by one or more    Z⁴; or-   (d) substituted by one or more substituents selected from Z³ and    substituted by —C₁₋₉alkyl optionally substituted by one or more Z⁴.

Particular compounds of formula I that may be mentioned include those inwhich:

E¹ is Y^(1a) or —C₁₋₆alkyl optionally substituted by one or more Y² andat least one of E², E³ and E⁴ represents Y^(1b) or —C₁₋₆alkyl optionallysubstituted by one or more Y².

Preferred compounds of formula I that may be mentioned include those inwhich:

E¹ is Y^(1a) or —C₁₋₃alkyl optionally substituted by one or more Y² andat least one of E² and E⁴ represents Y^(1b), —C₁₋₃alkyl optionallysubstituted by one or more Y².

Particular compounds of formula I that may be mentioned include those inwhich R¹ represents heteroaryl.

Preferred compounds of formula I where R¹ represents heteroaryl that maybe mentioned are those where R¹ represents benzofuranyl,benzothiophenyl, dihydrobenzofuranyl, indazolyl, indolyl, isoquinolinyl,isoxazolyl, pyridinyl, pyrrolyl and quinolinyl.

Particularly preferred compounds of formula I where R¹ representsheteroaryl that may be mentioned are those where R¹ representsbenzofuran-3-yl, benzothiophen-3-yl, dihydrobenzofuran-7-yl, indol-3-yl,indol-4-yl, indol-5-yl, isoquinolin-4-yl, isoxazol-4-yl, pyridin-3-yl,pyridin-4-yl, pyrrol-2-yl and quinolin-5-yl.

For example, compounds of formula I that may be mentioned include thosein which R¹ represents indolyl, e.g. indol-3-yl, indol-4-yl orindol-5-yl, where the indolyl is optionally substituted on the nitrogenwith —S(O)₂Ar^(x), where Ar^(x) is aryl or heteroaryl, preferablyoptionally substituted phenyl, e.g. unsubstituted phenyl or phenylsubstituted in the 4-position by —F, —Cl, —CH₃ or —CF₃.

Particular compounds of formula I that may be mentioned include those inwhich

R¹ is represented by

where:E², E³ and E⁴ represent hydrogen andE¹ represents hydrogen, or more preferably —F, —Cl, —CH₃, —CF₃, CN or—OCH₃; orE¹, E³ and E⁴ represent hydrogen andE² represents —F, —Cl, —CH₃, —CF₃, —CH═CHC(O)OCH₃, —CH₂NH₂, —CN,—CH₂N(H)C(O)CH═CH₂, —CH₂OH, —C(O)N(H)(4-methylphenyl), —N(H)C(O)CH₃,—N(H)C(O)CH═CH₂, —N(H)C(O)CH═CHCH₂NMe₂, —N(H)C(O)CH═CHPh, —N(H)C(O)C≡CH,—N(H)C(O)(2-hydroxyphenyl), —N(H)C(O)(6-hydroxypyrid-2-yl),—N(H)C(O)(5-chloro-2-hydroxyphenyl),—N(H)C(O)CH₂CH₂C(O)(1-pyrrolidinyl), —N(H)C(O)CH₂(OH),—N(H)C(O)CH(OH)Ph, —N(H)C(O)C(O)CH₃, —N(H)C(O)C(O)Ph, —N(H)S(O)₂CH═CH₂,or —OCH₃; orE¹, E² and E⁴ represent hydrogen andE³ represent —F, —Cl, —CH₃, —CF₃, —C(CH₃)₃, —CH═CH₂, —CH═CHC(O)OH,—CH═CHC(O)OCH₃, —CH₂NH₂, —CN, —CH₂N(H)C(O)CH═CH₂, —CH₂OH, —C(O)H,C(O)CH₃, —C(O)CF₃, —C(O)N(H)CH₃, —C(O)N(H)CH₂(2-furanyl),—C(O)(4-morpholinyl), —C(O)OH, —C(O)OCH₃, —N(H)C(O)CH₃, —N(H)C(O)CH═CH₂,—N(H)S(O)₂CH₃, —OCH(CH₃)₂, —OCH₃, —OCF₃, —S(O)₂CH₃, or—S(O)₂(4-morpholinyl).

Other particular compounds of formula I that may be mentioned includethose in which R¹ is represented by

where:E³ and E⁴ represent hydrogen; andE¹ represents —F and E² represent —F, —Cl, —CH₃ or —CF₃; orE¹ represents —Cl and E² represents —F, —Cl, —CH₃ or —CF₃; orE¹ represents —CH₃ and E² represents —F, —Cl, —CH₃, —CF₃, —CN or—N(H)C(O)CH═CH₂; orE² and E⁴ represent hydrogen; andE¹ represents —F and E³ represents —F or phenyl; orE¹ represents —Cl and E³ represents —F or —Cl; orE¹ represents —CH₃ and E³ represents —Cl or —OCH₂phenyl; orE¹ represents —OCH₃ and E³ represents —F; orE² and E³ represent hydrogen; andE¹ represents —F and E⁴ represents —Cl, —CH₃ or —CN; orE¹ represents —Cl and E⁴ represent —F, —Cl, —CH₃, —CF₃ or —OCH₃; orE¹ represents —CH₃ and E⁴ represent —F, —Cl, —CH₃, —CF₃, —CN,—N(H)C(O)CH═CH₂ or —S(O)₂(4-morpholinyl); orE¹ represents —CF₃ and E⁴ represents —F or —CF₃; orE¹ represents —CN and E⁴ represents —Cl; orE¹ represents —OCH₃ and E⁴ represents —F, —Cl, Br, —CH₃, —CH(CH₃)₂,—C(CH₃)₃, —CN or —OCH₃; orE¹ and E⁴ represent hydrogen; andE² represents —F and E³ represents —F, —Cl, —OH or —OCH₃; orE² represents —Cl and E³ represents —F or —C(O)(4-morpholinyl); orE² represents —CH₃ and E³ represents —F or —OCH₃; orE¹ represents —OCH₃ and E³ represents —OH; orE¹ represents-CH₂OCH₃ and E³ represents (piperidin-4-yl)methoxy or((1-tertbutoxycarbonyl)piperidin-4-yl)methoxy; orE¹ and E³ represent hydrogen; andE² and E⁴ represent —F; orE² and E⁴ represent —CF₃; orE⁴ represents hydrogen; andE¹, E² and E³ represent —F; orE¹ and E² represent —Cl and E³ represents —Cl, —OH or —OCH₃; orE¹ and E² represent —CH₃ and E³ represents —F or —OCH₃; orE² and E³ represent —Cl and E¹ represents —CH₃; orE² represents hydrogen; andE¹, E³ and E⁴ represent —F; orE³ and E⁴ represent —Cl and E¹ represents —CH₃; orE¹ and E⁴ represent —Cl and E¹ represents —OCH₃; orE¹ and E⁴ represent —CH₃ and E³ represents —F, —CH₃ or —OCH₃; orE¹ represents —F, E³ represents —CH₃ and E⁴ represents —Cl; orE¹ represents —Cl, E³ represents —F and E⁴ represents —CH₃; orE¹ represents —Cl, E³ represents —CH₃ and E⁴ represents —F; orE¹ and E⁴ represent —CH₃ and E³ represents —F; orE¹ represents —CH₃, E⁴ represents —Cl and E³ represents —CF₃ or —OCH₃;orE¹ represents hydrogen; andE² and E⁴ represent —CH₃ and E³ represents —OH; orE³ represents hydrogen; andE¹ and E² represent —Cl and E⁴ represents —CH₃.

Preferred particular compounds of formula I that may be mentionedinclude those in which R¹ is represented by

where:E¹, E³ and E⁴ represent hydrogen andE² represents —CH═CHC(O)OCH₃, —CH₂NH₂, —CH₂N(H)C(O)CH═CH₂, —CH₂OH,—N(H)C(O)CH═CH₂, —N(H)C(O)CH═CHCH₂NMe₂, —N(H)C(O)CH═CHPh, —N(H)C(O)C≡CH,—N(H)C(O)CH₂(OH), —N(H)C(O)CH(OH)Ph, —N(H)C(O)C(O)CH₃, —N(H)C(O)C(O)Phor —N(H)S(O)₂CH═CH₂; orE¹, E² and E⁴ represent hydrogen andE³ represents —CH═CH₂, —CH═CHC(O)OH, —CH═CHC(O)OCH₃, —CH₂NH₂,—CH₂N(H)C(O)CH═CH₂, —CH₂OH, —C(O)H, —C(O)CH₃, —C(O)CF₃, —N(H)C(O)CH═CH₂;orE³ and E⁴ represent hydrogen; andE¹ represents —F and E² represents —F, —Cl, or —CF₃; orE¹ represents —Cl and E² represents —Cl, —CH₃ or —CF₃; orE¹ represents —CH₃ and E² represents —Cl, —CH₃, —CN or —N(H)C(O)CH═CH₂;orE² and E⁴ represent hydrogen; andE¹ and E³ represent —F; orE¹ represents —Cl and E³ represents —F or —Cl; orE¹ represents —CH₃ and E³ represents —Cl; orE² and E³ represent hydrogen; andE¹ represents —F and E⁴ represents —Cl, —CH₃ or —CN; orE¹ represents —Cl and E⁴ represents —F, —Cl, —CH₃ or —CF₃; orE¹ represents —CH₃ and E⁴ represent, —Cl, —CH₃, —CF₃, —CN or—N(H)C(O)CH═CH; orE¹ represents —CF₃ and E⁴ represents —F or —CF₃; orE¹ represents —CN and E⁴ represents —Cl; orE⁴ represents hydrogen; andE¹, E² and E³ represent —F; orE¹ and E² represent —CH₃ and E³ represents —F₃; orE² and E³ represent —Cl and E¹ represents —CH₃; orE² represents hydrogen; andE¹, E³ and E⁴ represent —F; orE³ and E⁴ represent —Cl and E¹ represents —CH₃; orE¹ and E⁴ represent —CH₃ and E³ represents —F or —CH₃; orE¹ represents —F, E³ represents —CH₃ and E⁴ represents —Cl; orE¹ represents —Cl, E³ represents —F and E⁴ represents —CH₃; orE¹ represents —Cl, E³ represents —CH₃ and E⁴ represents —F; orE¹ and E⁴ represent —CH₃ and E³ represents —F; orE¹ represents —CH₃, E³ represents —CF₃ and E⁴ represents —Cl; orE¹ represents hydrogen; andE² and E⁴ represent —CH₃ and E³ represents —OH; orE³ represents hydrogen; andE¹ and E² represent —Cl and E⁴ represents —CH₃.

Preferred compounds of formula I that may be mentioned include those inwhich:

(a) Z¹ is not present or is selected from —F, —CN, —C(O)R^(b2),—C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2),—N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionallysubstituted by one or more substituents selected from W⁵, arylrepresented by

orheteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or onesulfur atom and optionally substituted by one or more substituentsselected from W⁶; or(b) Z² is not present or is selected from —F, —R^(a2),—C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2),—N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2),—N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from VV.

Other preferred compounds of formula I that may be mentioned includethose in which:

(a) Z³ is not present or is selected from —F, —R^(a2),—C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2),—N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2),—N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶; and/or(b) Z⁴ is not present or is selected from —F, —C(O)N(R^(c2))R^(d2),—N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionallysubstituted by one or more substituents selected from W⁵, aryloptionally substituted by one or more substituents selected from W⁶, orheteroaryl optionally substituted by one or more substituents selectedfrom W⁶.

Particularly preferred compounds of formula I that may be mentionedinclude those in which Z¹ represents —F, —CN, —C(O)NH₂,—C(O)N(R^(c2))R^(d2), —C(O)-(4-morpholinyl), —C(O)OEt, —N(H)C(O)Me,—N(H)C(O)R^(i2), —N(H)C(O)CH₂NMe₂, —N(H)C(O)OCMe₃, —N(H)C(O)OCH₂Ph,—N(Me)C(O)OCMe₃, —N(H)C(O)N(H)Me, —N(H)C(O)N(H)CHMe₂, —N(H)S(O)₂Me,—OMe, —OCF₃ and —OEt.

Preferred compounds of formula I where Z¹ represents heterocycloalkylthat may be mentioned are those where Z¹ represents dihydropyridinyl,imidazolinyl, morpholinyl, oxanyl, piperazinyl, piperidinyl,pyrrolidinyl and quinuclidinyl, wherein the heterocycloalkyl isoptionally substituted by one or more substituents selected from W⁵.

Preferred compounds of formula I where Z¹ represents

that may be mentioned are those where each W⁷, W¹⁰ and W¹¹ independentlyrepresents hydrogen, halogen, —R^(a3) or —CN; and one of W⁸ and W⁹represents hydrogen, halogen, —R^(a3) or —CN and the other representshalogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3),—N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², or heteroaryl optionally substituted byone or more substituents selected from G².

Particularly preferred compounds of formula I where Z¹ represents

that may be mentioned are those where each W⁷, W¹⁰ and W¹¹ independentlyrepresents —F, —Cl, —CH₃, —CF₃, or more preferably, hydrogen; and one ofW⁸ and W⁹ (preferably W⁸) represents —F, —Cl, —CH₃, —CF₃, or morepreferably, hydrogen, and the other (preferably W⁹) represents halogen,—R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3),—N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(n3))S(O)₂R^(o3), —OR^(q3x),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², or heteroaryl optionally substituted byone or more substituents selected from G².

For example, particular compounds of formula I that may be mentionedinclude those wherein:

(a) W⁸, W⁹, W¹⁰ and W¹¹ represents hydrogen and W⁷ represents —Cl or—S(O)₂CH₃; or(b) W⁷, W⁹, W¹⁰ and W¹¹ represents hydrogen and W⁸ represents —F, —Br,—CN, —N(H)C(O)CH₃, —OCH₃ or —S(O)₂CH₃; or(c) W⁷, W¹⁰ and W¹¹ represents hydrogen and:

-   -   (i) W⁸ and W⁹ represents —F or —Cl; or    -   (ii) W⁸ represents —F and W⁹ represents —CH₃.

More particularly preferred compounds of formula I where Z¹ represents

that may be mentioned are those where W⁷, W⁸, W¹⁰ and W¹¹ are hydrogenand W⁹ represents halogen, —R^(a3), —CN, —C(O)R^(b3),—C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3),—N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x),—S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionallysubstituted by one or more substituents selected from G¹, aryloptionally substituted by one or more substituents selected from G², orheteroaryl optionally substituted by one or more substituents selectedfrom G².

For example, more particularly preferred compounds of formula I that maybe mentioned are those where W⁷, W⁸, W¹⁰ and W¹¹ are hydrogen and W⁹represents —F, —Cl, —CH₃, cyclopropyl, —CF₃, —CN, —NH₂, —N(CH₃)₂,—N(H)C(O)CH₃, —N(H)C(O)OC(CH₃)₃, —SO₂CH₃, —SO₂NH₂, —S(O)₂N(CH₃)₂,—S(O)₂-4-morpholinyl, 4-methylpiperazin-1-yl,4-methylpiperidin-1-ylmethyl and 1,2,3-thiadiazol-4-yl.

Preferred compounds of formula I where Z¹ represents heteroaryl that maybe mentioned are those where Z¹ represents benzimidazolyl,benzodioxinyl, benzoxazolyl, furanyl, imidazolyl, imidazopyridinyl,indolyl, isoquinolinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridyl, pyrrolopyridinyl, quinolinyl, thiazolyl, thiophenyl andtriazolyl, wherein the heteroaryl is optionally substituted by one ormore substituents selected from W⁶.

Particularly preferred compounds of formula I where Z¹ representsheteroaryl that may be mentioned are those where Z¹ representsbenzimidazol-2-yl, 1,4-benzodioxin-2-yl, benzoxazol-2-yl, furan-2-yl,imidazol-1-yl, imidazol-4-yl, imidazo-[1,2-a]pyridin-2-yl, indol-3-yl,indol-5-yl, isoquinolin-4-yl, 1,3,4-oxadiazol-2-yl, 1,2-oxazol-4-yl,pyrazin-3-yl, pyrazol-1-yl, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 5H,6H,7H-pyrrolo[3,4-b]pyridin-5-yl, thiazol-5-yl,thiophen-2-yl, 1,2,3-triazol-4-yl and 1,2,4-triazol-3-yl, wherein theheteroaryl is optionally substituted by one or more substituentsselected from WP.

More particularly preferred compounds of formula I that may be mentionedare those where W⁶ represents —F, —Cl, —Br, —CH₃, cyclopropyl, —CF₃,—CN, —NH₂, —N(CH₃)₂, —SO₂CH₃, —SO₂NH₂ and —SO)₂N(CH₃)₂.

In another embodiment of the invention there is provided a compound offormula

wherein:R¹ represents:indanyl, naphthyl, tetrahydronaphthyl or heteroaryl, the latterconnected to the pyrimidine of formula I via a carbon atom of theheteroaryl ring, which indanyl, naphthyl, tetrahydronaphthyl andheteroaryl rings are optionally substituted by one or more substituentsselected from Y¹, —C₁₋₆alkyl optionally substituted by one or more Y²and heterocycloalkyl optionally substituted by one or more Y³; or arylrepresented by

E¹, E², E³ and E⁴ represents hydrogen, Y¹, —C₁₋₆alkyl optionallysubstituted by one or more Y² or heterocycloalkyl optionally substitutedby one or more Y³, but where at least one of E¹, E², E³ and E⁴ is otherthan hydrogen;R² represents hydrogen, halogen or —C₁₋₁₂alkyl optionally substituted byone or more Z¹;R³ represents —C₁₋₁₂alkyl substituted by one or more Z¹ orheterocycloalkyl optionally substituted by one or more Z²; orR² and R³ are linked together to form, along with the atoms to whichthey are attached, a 5- to 8-membered non-aromatic ring, wherein thelink formed by R² and R³ is optionally substituted by one or moresubstituents selected from Z³ or —C₁₋₉alkyl optionally substituted byone or more Z⁴;each Y¹ independently represents halogen, —CN, —C(O)R^(a),—C(O)N(R^(b))R^(c), —C(O)OR^(d),—N(R^(e))R^(f), —N(R^(g))C(O)R^(h), —N(R^(i))C(O)OR^(j),—N(R^(k))C(O)N(R^(l))R^(m), —NO₂, —N(R^(n))S(O)₂R^(o), —OR^(p),—OC(O)R^(q), —OS(O)₂R^(r), —S(O)_(m)R^(s), —S(O)₂N(R^(t))R^(u),heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³, or heteroaryl optionally substituted byone or more substituents selected from W³;each R^(a), R^(b), R^(c), R^(d), R^(e), R^(g), R^(h), R^(i), R^(k),R^(l), R^(m), R^(n), R^(p), R^(q), R^(s), R^(t) and R^(u) independentlyrepresents hydrogen, —C₁₋₆ alkyl optionally substituted by one or moresubstituents selected from W¹, heterocycloalkyl optionally substitutedby one or more substituents selected from W², aryl optionallysubstituted by one or more substituents selected from W³, or heteroaryloptionally substituted by one or more substituents selected from W³; orany two R^(b) and R^(c), R^(e) and R^(f), R^(i) and R^(m) and/or R^(t)and R^(u) are linked together to form, along with the nitrogen atom towhich they are attached, a 3- to 8-membered monocyclic or bicyclic ring,which ring optionally contains one or two heteroatoms and which ringoptionally is substituted by one or more substituents selected from W²,C₁₋₃alkyl optionally substituted by one or more substituents selectedfrom W¹, and ═O;each R^(f), R^(j), R^(o) and R^(r) independently represent —C₁₋₆ alkyloptionally substituted by one or more substituents selected from W¹,heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³ or heteroaryl optionally substituted byone or more substituents selected from W³;each Y² independently represents halogen, —CN, —C(O)R^(b1),—C(O)N(R^(c1))R^(d1), —C(O)OR^(e1), —N(R^(f1))R^(g1),—N(R^(h1))C(O)R^(i1), —N(R^(j1))C(O)OR^(k1),—N(R^(l1))C(O)N(R^(m1))R^(n1), —N(R^(o1))S(O)₂R^(p1), —OR^(q1),—OC(O)R^(r1), —OS(O)₂R^(s1), —S(O)_(m)R^(t1), —S(O)₂N(R^(u1))R^(v1),heterocycloalkyl optionally substituted by one or more substituentsselected from W¹, aryl optionally substituted by one or moresubstituents selected from W², heteroaryl optionally substituted by oneor more substituents selected from W²;each Y³ independently represents halogen, —R^(a1), —CN, —C(O)R^(b1),—C(O)N(R^(c1))R^(d1), —C(O)OR^(e1), —N(R^(f1))R^(g1),—N(R^(h1))C(O)R^(i1), —N(R^(j1))C(O)OR^(k1),—N(R^(l1))C(O)N(R^(m1))R^(n1), —N(R^(o1))S(O)₂R^(p1), —OR^(q1),—OC(O)R^(r1), —OS(O)₂R^(s1), —S(O)_(m)R^(t1), —S(O)₂N(R^(u1))R^(v1),heterocycloalkyl optionally substituted by one or more substituentsselected from W¹, aryl optionally substituted by one or moresubstituents selected from W², heteroaryl optionally substituted by oneor more substituents selected from W², or ═O;each R^(a1), R^(b1), R^(c1), R^(d1), R^(e1), R^(f1), R^(h1), R^(i1),R^(j1), R^(l1), R^(m1), R^(n1), R^(o1), R^(q1), R^(r1), R^(t1), R^(u1)and R^(v1) independently represents hydrogen, C₁₋₆ alkyl optionallysubstituted by one or more substituents selected from W¹,heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³, or heteroaryl optionally substituted byone or more substituents selected from W³; orany two R^(c1), R^(d1), R^(f1) and R^(g1), R^(m1) and R^(n1), and/orR^(u1) and R^(v1) are linked together to form, along with the nitrogenatom to which they are attached, a 3- to 8-membered monocyclic orbicyclic ring, which ring optionally contains one or two heteroatoms andwhich ring optionally is substituted by one or more substituentsselected from W², C₁₋₃alkyl optionally substituted by one or moresubstituents selected from W¹, and ═O;each R^(g1), R^(k1), R^(p1) and R^(s1) independently represent —C₁₋₆alkyl optionally substituted by one or more substituents selected fromW¹, heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³, or heteroaryl optionally substituted byone or more substituents selected from W³;each Z¹ independently represents halogen, —CN, —C(O)R^(b2),—C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2),—N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl represented by

heteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or onesulfur atom and optionally substituted by one or more substituentsselected from W⁶;each Z² and Z³ independently represents halogen, —R^(a2), —CN,—C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2),—N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶;each Z⁴ independently represents halogen, —CN, —C(O)R^(b2),—C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2),—N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, heteroaryl optionally substituted by oneor more substituents selected from W⁶, or ═O;each R^(a2), R^(b2), R^(c2), R^(d2), R^(e2), R^(f2), R^(h2), R^(i2),R^(j2), R^(l2), R^(m2), R^(n2), R^(o2), R^(r2), R^(t2), R^(u2) andR^(v2) independently represents hydrogen or C₁₋₆ alkyl optionallysubstituted by one or more substituents selected from W⁴,heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶; orany two R^(c2) and R^(d2), R^(f2) and R^(g3), R^(m2) and R^(n2) and/orR^(u2) and R^(v2) are linked together to form, along with the nitrogenatom to which they are attached, a 3- to 8-membered monocyclic orbicyclic ring, which ring optionally contains one or two heteroatoms andwhich ring optionally is substituted by one or more substituentsselected from W⁵, C₁₋₃alkyl optionally substituted by one or moresubstituents selected from W⁴, and ═O;each R^(g2), R^(k2), R^(p2), R^(q2) and R^(s2) independently represent—C₁₋₆ alkyl optionally substituted by one or more substituents selectedfrom W⁴, heterocycloalkyl optionally substituted by one or moresubstituents selected from W⁵, aryl optionally substituted by one ormore substituents selected from W⁶, or heteroaryl optionally substitutedby one or more substituents selected from W⁶; each W¹ and W⁴independently represents halogen, —CN, —N(V)R^(g3),—N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², heteroaryl optionally substituted by oneor more substituents selected from G², or ═O;each W², W³, W⁵ and W⁸ independently represents halogen, —R^(a3), —CN,—C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3),—N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², heteroaryl (optionally substituted by oneor more substituents selected from G², or ═O;W⁷ and W¹¹ represents hydrogen;each W⁸ and W¹⁰ independently represents hydrogen, halogen, —R^(a3),—CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3),—N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², or heteroaryl optionally substituted byone or more substituents selected from G²;W⁹ represents halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3),—C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3),—N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3),—N(R^(o3))S(O)₂R^(p3), —OR^(q3x), —OC(O)R^(r3), —OS(O)₂R^(s3),—S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionallysubstituted by one or more substituents selected from G¹, aryloptionally substituted by one or more substituents selected from G², orheteroaryl optionally substituted by one or more substituents selectedfrom G²;each R^(a3), R^(b3), R^(c3), R^(d3), R^(e3), R^(f3), R^(h3), R^(i3),R^(j3), R^(l3), R^(m3), R^(n3), R^(o3), R^(q3), R^(r3), R^(t3), R^(u3)and R^(v3) independently represents hydrogen or —C₁₋₆ alkyl optionallysubstituted by one or more G³; orany two R^(c3) and R^(d3), R^(f3) and R^(g3), R^(m3) and R^(n3) and/orR^(u3) and R^(v3) are linked together to form, along with the nitrogenatom to which they are attached, a 4- to 6-membered ring, which ringoptionally contains one heteroatom and which ring optionally issubstituted by one or more G²;each R^(g3), R^(k3), R^(p3), R^(q3) and R^(s3) independently representC₁₋₆ alkyl optionally substituted by one or more G³;R^(q3x) represents C₂₋₆ alkyl optionally substituted by one or more G³;each G¹ and G² independently represents halogen, —R^(a4), —CN,—C(O)R^(b4), —C(O)N(R^(c4))R^(d4), —C(O)OR^(e4), —N(R^(f4))R^(g4),—N(R^(h4))C(O)R^(i4), —N(R^(j4))C(O)OR^(k4),—N(R^(l4))C(O)N(R^(m4))R^(n4), —N(R^(o4))S(O)₂R^(p4), —OR^(q4),—OC(O)R^(r4), —OS(O)₂R^(s4), —S(O)_(m)R^(t4), —S(O)₂N(R^(u4))R^(v4), or═O;G³ represents halogen, —CN, —C(O)R^(b4), —C(O)N(R^(c4))R^(d4),—C(O)OR^(e4), —N(R^(f4))R^(g4), —N(R^(h4))C(O)R^(i4),—N(R^(j4))C(O)OR^(k4), —N(R^(l4))C(O)N(R^(m4))R^(n4),—N(R^(o4))S(O)₂R^(p4), —OR^(q4), —OC(O)R^(r4), —OS(O)₂R^(s4),—S(O)_(m)R^(t4), —S(O)₂N(R^(u4))R^(v4), or ═O;each R^(a4), R^(b4), R^(c4), R^(d4), R^(e4), R^(f4), R^(h4), R^(i4),R^(j4), R^(l4), R^(m4), R^(n4), R^(o4), R^(q4), R^(r4), R^(t4), R^(u4)and R^(v4) independently represents hydrogen or —C₁₋₆ alkyl optionallysubstituted by one or more —F; orany two R^(c4) and R^(d4), R^(f4) and R^(g4), R^(m4) and R^(n4) and/orR^(ua) and R^(v4) are linked together to form, along with the nitrogenatom to which they are attached, a 3- to 6-membered ring, which ringoptionally substituted by one or more —F, —CH₃, —CH₂CH₃, —CHF₂, —CF₃,—CH₂CF₃, or ═O;each R^(g4), R^(k4), R^(p4) and R^(s4) independently represent C₁₋₆alkyl optionally substituted by one or more —F;each m independently represents 0, 1 or 2;provided that formula I does not represent

-   6-(3-pyridinyl)-N⁴-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,4-pyrimidinediamine,-   6-(3-pyridinyl)-N⁴-[[5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2-pyridinyl]methyl]-2,4-pyrimidinediamine,-   6-(3-pyridinyl)-N⁴-[[5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2-pyrimidinyl]-methyl]-2,4-pyrimidinediamine,-   N⁴-[2-(diethylamino)ethyl]-6-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine,    N⁴-[3-(4-morpholinyl)propyl]-6-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine,    or-   N⁴-[2-(4-morpholinyl)ethyl]-6-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;    or a pharmaceutically acceptable salt thereof;    which compounds may be referred to herein as “the compounds of the    invention”.

Pharmaceutically-acceptable salts include acid addition salts and baseaddition salts. Such salts may be formed by conventional means, forexample by reaction of a free acid or a free base form of a compound offormula I with one or more equivalents of an appropriate acid or base,optionally in a solvent, or in a medium in which the salt is insoluble,followed by removal of said solvent, or said medium, using standardtechniques (e.g. in vacuo, by freeze-drying or by filtration). Salts mayalso be prepared by exchanging a counter-ion of a compound of theinvention in the form of a salt with another counter-ion, for exampleusing a suitable ion exchange resin. For the avoidance of doubt,solvates are also included within the scope of the invention.

Compounds of the invention may contain double bonds and may thus existas E (entgegen) and Z (zusammen) geometric isomers about each individualdouble bond. All such isomers and mixtures thereof are included withinthe scope of the invention.

Compounds of the invention may also exhibit tautomerism. All tautomericforms and mixtures thereof are included within the scope of theinvention.

Compounds of the invention may also contain one or more asymmetriccarbon atoms and may therefore exhibit optical and/ordiastereoisomerism. Diastereoisomers may be separated using conventionaltechniques, e.g. chromatography or fractional crystallisation. Thevarious stereoisomers may be isolated by separation of a racemic orother mixture of the compounds using conventional, e.g. fractionalcrystallisation or HPLC, techniques. Alternatively the desired opticalisomers may be made by reaction of the appropriate optically activestarting materials under conditions which will not cause racemisation orepimerisation (i.e. a ‘chiral pool’ method), by reaction of theappropriate starting material with a ‘chiral auxiliary’ which cansubsequently be removed at a suitable stage, by derivatisation (i.e. aresolution, including a dynamic resolution), for example with ahomochiral acid followed by separation of the diastereomeric derivativesby conventional means such as chromatography, or by reaction with anappropriate chiral reagent or chiral catalyst all under conditions knownto the skilled person. All stereoisomers and mixtures thereof areincluded within the scope of the invention.

Unless otherwise specified, C_(1-q) alkyl groups (where q is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number (i.e. a minimum of two or three, as appropriate)of carbon atoms, be branched-chain, and/or cyclic (so forming aC_(3-q)-cycloalkyl group). When there is a sufficient number (i.e. aminimum of four) of carbon atoms, such groups may also be part cyclic.Such alkyl groups may also be saturated or, when there is a sufficientnumber (i.e. a minimum of two) of carbon atoms, be unsaturated (forming,for example, a C_(2-q) alkenyl or a C_(2-q) alkynyl group).

Unless otherwise specified, C_(1-q) alkylene groups (where q is theupper limit of the range) defined herein may (in a similar manner to thedefinition of C_(1-q) alkyl) be straight-chain or, when there is asufficient number (i.e. a minimum of two or three, as appropriate) ofcarbon atoms, be branched-chain, and/or cyclic (so forming aC_(3-q)-cycloalkylene group). When there is a sufficient number (i.e. aminimum of four) of carbon atoms, such groups may also be part cyclic.Such alkylene groups may also be saturated or, when there is asufficient number (i.e. a minimum of two) of carbon atoms, beunsaturated (forming, for example, a C_(2-q)alkenylene or aC_(2-q)alkynylene group). Particular alkylene groups that may bementioned include those that are straight-chained and saturated.

The term “halo”, when used herein, includes fluoro, chloro, bromo andiodo (for example, fluoro and chloro).

Heterocycloalkyl groups that may be mentioned include non-aromaticmonocyclic and bicyclic heterocycloalkyl groups (which groups mayfurther be bridged) in which at least one (e.g. one to four) of theatoms in the ring system is other than carbon (i.e. a heteroatom), andin which the total number of atoms in the ring system is between threeand twelve (e.g. between five and ten and, most preferably, betweenthree and eight, e.g. a 5- or 6-membered heterocycloalkyl group).Further, such heterocycloalkyl groups may be saturated or unsaturatedcontaining one or more double and/or triple bonds, forming for example aC_(2-q) (e.g. heterocycloalkenyl (where q is the upper limit of therange) or a C_(7-q) heterocycloalkynyl group. C_(2-q) heterocycloalkylgroups that may be mentioned include 7-azabicyclo-[2.2.1]heptanyl,6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl,8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl,dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl),dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyland 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl(including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl,7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl, oxetanyl,oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl,pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl,3-sulfolenyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyridyl(such as 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl),thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including1,3,5-trithianyl), tropanyl and the like. Substituents onheterocycloalkyl groups may, where appropriate, be located on any atomin the ring system including a heteroatom. Further, in the case wherethe substituent is another cyclic compound, then the cyclic compound maybe attached through a single atom on the heterocycloalkyl group, forminga so-called “spiro”-compound. The point of attachment ofheterocycloalkyl groups may be via any atom in the ring system including(where appropriate) a heteroatom (such as a nitrogen atom), or an atomon any fused carbocyclic ring that may be present as part of the ringsystem. Heterocycloalkyl groups may also be in the N- or S-oxidisedform. At each occurrence when mentioned herein, a heterocycloalkyl groupis preferably a 3- to 8-membered heterocycloalkyl group (e.g. a 5- or6-membered heterocycloalkyl group).

The term “aryl”, when used herein, includes C₆₋₁₄ (e.g. C₆₋₁₀) aromaticgroups. Such groups may be monocyclic or bicyclic and, when bicyclic, beeither wholly or partly aromatic. C₆₋₁₀ aryl groups that may bementioned include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl,and the like (e.g. phenyl, naphthyl and the like). For the avoidance ofdoubt, the point of attachment of substituents on aryl groups may be viaany carbon atom of the ring system.

The term “heteroaryl” (or heteroaromatic), when used herein, includes 5-to 10-membered heteroaromatic groups containing one or more heteroatomsselected from oxygen, nitrogen and/or sulfur. Such heteroaryl group maycomprise one, or two rings, of which at least one is aromatic.Substituents on heteroaryl/heteroaromatic groups may, where appropriate,be located on any atom in the ring system including a heteroatom. Thepoint of attachment of heteroaryl/heteroaromatic groups may be via anyatom in the ring system including (where appropriate) a heteroatom.Bicyclic heteroaryl/heteroaromatic groups may comprise a benzene ringfused to one or more further aromatic or non-aromatic heterocyclicrings, in which instances, the point of attachment of the polycyclicheteroaryl/heteroaromatic group may be via any ring including thebenzene ring or the heteroaryl/heteroaromatic or heterocycloalkyl ring.Examples of heteroaryl/heteroaromatic groups that may be mentionedinclude pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl,thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, pyrimidinyl,indolyl, azaindolyl, pyrazinyl, indazolyl, pyrimidinyl, quinolinyl,isoquinolinyl, benzofuranyl, benzothiophenyl, benzoimidazolyl,benzoxazolyl, benzothiazolyl and benzotriazolyl. The oxides ofheteroaryl/heteroaromatic groups are also embraced within the scope ofthe invention (e.g. the N-oxide). As stated above, heteroaryl includespolycyclic (e.g. bicyclic) groups in which one ring is aromatic (and theother may or may not be aromatic). Hence, other heteroaryl groups thatmay be mentioned include e.g. benzo[1,3]dioxolyl, benzo[1,4]dioxinyl,indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl,1,2,3,4-tetra-hydroquinolinyl and the like.

Heteroatoms that may be mentioned include phosphorus, silicon, boronand, preferably, oxygen, nitrogen and sulfur.

For the avoidance of doubt, in cases in which the identity of two ormore substituents in a compound of the invention may be the same, theactual identities of the respective substituents are not in any wayinterdependent.

For the avoidance of doubt, when R¹ is defined as

it is connected to the rest of formula I by the bond interrupted by thewiggly line, and formula I can thus be represented by

Likewise, when R³ is —C₁₋₁₂ alkyl substituted by Z¹, and Z¹ isrepresented by

then, if e.g. R³ is C₂alkyl, then formula I can be represented by

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature (or the most abundant one found in nature). Allisotopes of any particular atom or element as specified herein arecontemplated within the scope of the compounds of the invention. Hence,the compounds of the invention also include deuterated compounds, i.e.in which one or more hydrogen atoms are replaced by the hydrogen isotopedeuterium.

All individual features (e.g. preferred features) mentioned herein maybe taken in isolation or in combination with any other feature(including preferred features) mentioned herein (hence, preferredfeatures may be taken in conjunction with other preferred features, orindependently of them).

The skilled person will appreciate that compounds of the invention thatare the subject of this invention include those that are stable. Thatis, compounds of the invention include those that are sufficientlyrobust to survive isolation from e.g. a reaction mixture to a usefuldegree of purity.

Particular compounds of formula I that may be mentioned include those inwhich:

R² represents hydrogen or —C₁₋₁₂alkyl optionally substituted by one ormore Z¹; andR³ represents —C₁₋₁₂alkyl substituted by one or more Z¹ orheterocycloalkyl optionally substituted by one or more Z².

For example, compounds of formula I that may be mentioned include thosein which R² represents methyl, or preferably, hydrogen and R³represents:

(a) —C₁₋₁₂alkyl (for example —C₁₋₆alkyl) substituted by two, orpreferably, one Z¹ or;(b) —C₂₋₆alkyl substituted by two, or preferably, one Z¹ orheterocycloalkyl optionally substituted by two, or preferably, one Z²;or(c)

(d) —C₁₋₁₂alkyl (for example —C₁₋₆alkyl) substituted by heteroarylhaving 1 to 3 nitrogen atoms, one oxygen atom and/or one sulfur atom andwhich heteroaryl is optionally substituted by one or more substituentsselected from W³; or(e) —C₃₋₆alkyl or a heterocycloalkyl selected from cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl,cyclopropylpropyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinylwherein the C₃₋₆alkyl is substituted by two, or preferably, one Z¹ andthe heterocycloalkyl is optionally substituted by two, or preferably,one Z².

Particular compounds of formula I that may be mentioned include those inwhich: R² and R³ are linked together to form, along with the atoms towhich they are attached, a 5- to 8-membered non-aromatic ring, whereinthe link formed by R² and R³ is optionally substituted by one or moresubstituents selected from Z³ or —C₁₋₉alkyl optionally substituted byone or more Z⁴.

For example, compounds of formula I that may be mentioned include thosein which R² and R³ are linked together to form, along with the atoms towhich they are attached, a 5- to 6-membered non-aromatic ring, whereinthe non-aromatic ring is:

-   (a) unsubstituted; or-   (b) substituted by one or more substituents selected from Z³; or-   (c) substituted by —C₁₋₉alkyl optionally substituted by one or more    Z⁴; or-   (d) substituted by one or more substituents selected from Z³ and    substituted by —C₁₋₉alkyl optionally substituted by one or more Z⁴.

Particular compounds of formula I that may be mentioned include those inwhich R¹ represents heteroaryl.

Preferred compounds of formula I where R¹ represents heteroaryl that maybe mentioned are those where R¹ represents benzofuranyl,benzothiophenyl, dihydrobenzofuranyl, indazolyl, indolyl, isoquinolinyl,pyridinyl, pyrrolyl and quinolinyl.

Particularly preferred compounds of formula I where R¹ representsheteroaryl that may be mentioned are those where R¹ representsbenzofuran-3-yl, benzothiophen-3-yl, dihydrobenzofuran-7-yl, indol-3-yl,indol-4-yl, indol-5-yl, isoquinolin-4-yl, pyridin-3-yl, pyridin-4-yl,pyrrol-2-yl and quinolin-5-yl.

For example, compounds of formula I that may be mentioned include thosein which R¹ represents indolyl, e.g. indol-3-yl, indol-4-yl orindol-5-yl, where the indolyl is optionally substituted on the nitrogenwith —S(O)₂Ar^(x), where Ar^(x) is aryl or heteroaryl, preferablyoptionally substituted phenyl, e.g. unsubstituted phenyl or phenylsubstituted in the 4-position by —F, —Cl, —CH₃ or —CF₃.

Preferred compounds of formula I that may be mentioned include those inwhich R¹ is represented by

where:E², E³ and E⁴ represent hydrogen andE¹ represents —F, —Cl, —CH₃, —CF₃, CN or —OCH₃; orE¹, E³ and E⁴ represent hydrogen and E² represents —F, —Cl, —CH₃, —CF₃,—CN; orE¹, E² and E⁴ represent hydrogen and E³ represent —F, —Cl, —CH₃, —CF₃,—C(CH₃)₃, —CH═CH₂, —OCF₃, —S(O)₂CH₃, or —S(O)₂(4-morpholinyl).

Other preferred compounds of formula I that may be mentioned includethose in which R¹ is represented by

where:E³ and E⁴ represent hydrogen; andE¹ represents —F and E² represent —F, —Cl, —CH₃ or —CF₃; orE¹ represents —Cl and E² represents —F, —Cl, —CH₃ or —CF₃; orE¹ represents —CH₃ and E² represents —F, —Cl, —CH₃, —CF₃ or —CN; orE² and E⁴ represent hydrogen; andE¹ represents —Cl and E³ represents —F or —Cl; orE¹ represents —CH₃ and E³ represents —Cl; orE¹ represents —OCH₃ and E³ represents —F; orE² and E³ represent hydrogen; andE¹ represents —F and E⁴ represents —Cl, —CH₃ or —CN; orE¹ represents —Cl and E⁴ represent —F, —Cl, —CH₃, —CF₃ or —OCH₃; orE¹ represents —CH₃ and E⁴ represent —F, —Cl, —CH₃, —CF₃ or —CN; orE¹ represents —CF₃ and E⁴ represents —F or —CF₃; orE¹ represents —CN and E⁴ represents —Cl; orE¹ represents —OCH₃ and E⁴ represents —F, —Cl, Br, —CH₃, —CH(CH₃)₂,—C(CH₃)₃, —CN or —OCH₃; orE¹ and E⁴ represent hydrogen; andE² represents —F and E³ represents —F, —Cl, —OH or —OCH₃; orE² represents —Cl and E³ represents —F; orE² represents —CH₃ and E³ represents —F or —OCH₃; orE¹ represents —OCH₃ and E³ represents —OH; orE¹ and E³ represent hydrogen; andE² and E⁴ represent —F; orE² and E⁴ represent —CF₃; orE⁴ represents hydrogen; andE¹, E² and E³ represent —F; orE¹ and E² represent —Cl and E³ represents —Cl, —OH or —OCH₃; orE¹ and E² represent —CH₃ and E³ represents —F or —OCH₃; orE² and E³ represent —Cl and E¹ represents —CH₃; orE² represents hydrogen; andE¹, E³ and E⁴ represent —F; orE³ and E⁴ represent —Cl and E¹ represents —CH₃; orE¹ and E⁴ represent —Cl and E¹ represents —OCH₃; orE¹ and E⁴ represent —CH₃ and E³ represents —F, —CH₃ or —OCH₃; orE¹ represents —F, E³ represents —CH₃ and E⁴ represents —Cl; orE¹ represents —Cl, E³ represents —F and E⁴ represents —CH₃; orE¹ represents —Cl, E³ represents —CH₃ and E⁴ represents —F; orE¹ and E⁴ represent —CH₃ and E³ represents —F; orE¹ represents —CH₃, E⁴ represents —Cl and E³ represents —CF₃ or —OCH₃;orE¹ represents hydrogen; andE² and E⁴ represent —CH₃ and E³ represents —OH; orE³ represents hydrogen; andE¹ and E² represent —Cl and E⁴ represents —CH₃.

Preferred compounds of formula I that may be mentioned include those inwhich:

(a) Z¹ represents halogen, —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2),—C(O)OR^(e2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2),—N(R^(m2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionallysubstituted by one or more substituents selected from W⁵, arylrepresented by

orheteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or onesulfur atom and optionally substituted by one or more substituentsselected from W⁶; or(b) Z² is not present or is selected from —F, —R^(a2),—C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(n2))C(O)R^(i2),—N(R^(j2))C(O)0R^(k2), —N(R^(l2))C(o)N(R^(m2))R^(n2),—N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶.

Other preferred compounds of formula I that may be mentioned includethose in which:

(a) Z³ is not present or is selected from —F, —R^(a2),—C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2),—N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2),—N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶; and/or(b) Z⁴ is not present or is selected from —F, —C(O)N(R^(c2))R^(d2),—N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionallysubstituted by one or more substituents selected from W⁵, aryloptionally substituted by one or more substituents selected from W⁶, orheteroaryl optionally substituted by one or more substituents selectedfrom W⁶.

More particularly preferred compounds of formula I that may be mentionedinclude those in which Z¹ represents —F, —CN, —C(O)N(R^(c2))R^(d2),—N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(l2))C(O)N(R^(m2))R^(n2),—N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl represented by

orheteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or onesulfur atom and optionally substituted by one or more substituentsselected from W⁶.

Other more particularly preferred compounds of formula I that may bementioned include those in which Z¹ represents —C(O)N(R^(c2))R^(d2),—N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(l2))C(O)N(R^(m2))R^(n2),—N(R^(o2))S(O)₂R^(p2), —OR^(p), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2)or aryl represented by

Further compounds of formula I that may be mentioned include those inwhich

R^(c2), R^(f2), R^(h2), R^(l2), R^(m2), R^(o2), and R^(u2) representshydrogen; andR^(d2), R^(g2), R^(i2), R^(n2), R^(p2), R^(q2), R^(t2) and R^(v2)represents aryl optionally substituted by one or more substituentsselected from W⁶, or heteroaryl optionally substituted by one or moresubstituents selected from W⁶.

Preferred compounds of formula I that may be mentioned are those whereZ¹ represents —OR^(q2) and R^(q2) represents aryl optionally substitutedby one or more substituents selected from W⁶, or heteroaryl optionallysubstituted by one or more substituents selected from W⁶.

More preferred compounds of formula I that may be mentioned are thosewhere Z¹ represents —N(R^(f2))R^(g2), R^(f2) represents hydrogen andR^(g2) represents aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶.

Further preferred compounds of formula I that may be mentioned are thosewhere Z¹ represents —N(R^(o2))S(O)R^(p2), R^(o2) represents hydrogen andR^(p2) represents aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶.

Preferred compounds of formula I where Z¹ represents heterocycloalkylthat may be mentioned are those where Z¹ represents dihydropyridinyl,imidazolinyl, oxanyl, piperazinyl, piperidinyl, pyrrolidinyl andquinuclidinyl, wherein the heterocycloalkyl is optionally substituted byone or more substituents selected from W⁵.

Preferred compounds of formula I where Z¹ represents

that may be mentioned are those where:(a) each W⁸ and W¹⁰ are independently selected from —F, —CH₃, —CN, —CF₃,or more preferably hydrogen and W⁹ is selected from —R^(a3), —CN,—C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3),—N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², or heteroaryl optionally substituted byone or more substituents selected from G²; and(b) each W⁹ and W¹⁰ are independently selected from —F, —CH₃, —CN, —CF₃,or more preferably hydrogen and W⁸ is selected from —R^(a3), —CN,—C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3),—N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x),—OC(O)R^(i3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², or heteroaryl optionally substituted byone or more substituents selected from G².

For example, particular compounds of formula I that may be mentionedinclude those wherein W⁸ and W¹⁰ represents hydrogen and W⁹ represents—F, —CH₃, cyclopropyl, —CF₃, —CN, —NH₂, —N(CH₃)₂, —N(H)C(O)CH₃,—N(H)C(O)OC(CH₃)₃, —SO₂CH₃, —SO₂NH₂, —S(O)₂N(CH₃)₂,—S(O)₂-4-morpholinyl, 4-methylpiperazin-1-yl,4-methylpiperidin-1-ylmethyl and 1,2,3-thiadiazol-4-yl; or W⁹ and W¹⁰represents hydrogen and W^(e) represents —F, —Cl, —CN, —CH₃, —NMe₂,—S(O)₂NH₂ or —S(O)₂NMe₂.

Preferred compounds of formula I where Z¹ represents heteroaryl that maybe mentioned are those where Z¹ represents benzimidazolyl,benzodioxinyl, benzoxazolyl, imidazolyl, imidazopyridinyl, indolyl,isoquinolinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl,pyrrolopyridinyl, quinolinyl, thiazolyl, thiophenyl and triazolyl,wherein the heteroaryl is optionally substituted by one or moresubstituents selected from W⁶.

Particularly preferred compounds of formula I where Z¹ representsheteroaryl that may be mentioned are those where Z¹ representsbenzimidazol-2-yl, 1,4-benzodioxin-2-yl, benzoxazol-2-yl, imidazol-1-yl,imidazol-4-yl, imidazo[1,2-a]pyridin-2-yl, indol-3-yl, indol-5-yl,isoquinolin-4-yl, 1,3,4-oxadiazol-2-yl, 1,2-oxazol-4-yl, pyrazin-3-yl,pyrazol-1-yl, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,5H,6H,7H-pyrrolo[3,4-b]pyridin-5-yl, thiazol-5-yl, thiophen-2-yl,1,2,3-triazol-4-yl and 1,2,4-triazol-3-yl, wherein the heteroaryl isoptionally substituted by one or more substituents selected from VV.

More particularly preferred compounds of formula I that may be mentionedare those where W⁶ represents —F, —Cl, —Br, —CH₃, cyclopropyl, —CF₃,—CN, —NH₂, —N(CH₃)₂, —SO₂CH₃, —SO₂NH₂ and —SO)₂N(CH₃)₂.

In yet another embodiment of the invention there is provided a compoundof formula I,

wherein:R¹ represents heteroaryl connected to the pyrimidine of formula I via acarbon atom of the heteroaryl ring, which heteroaryl ring is substitutedby one or more substituents selected from Y¹, —C₁₋₆alkyl optionallysubstituted by one or more Y² 4846-3664-5703.1 and heterocycloalkyloptionally substituted by one or more Y³; or aryl represented by

E¹ represents Y^(1a) or —C₁₋₆alkyl optionally substituted by one or moreY²; and at least one of E², E³ and E⁴ represents Y^(1b) or —C₁₋₆alkyloptionally substituted by one or more Y²;R² represents hydrogen, halogen, —CN, —C₁₋₁₂alkyl optionally substitutedby one or more Z¹, or heterocycloalkyl optionally substituted by one ormore Z²;R³ represents —C₁₋₁₂alkyl optionally substituted by one or more Z¹ orheterocycloalkyl optionally substituted by one or more Z²; orR² and R³ are linked together to form, along with the atoms to whichthey are attached, a 5- to 8-membered non-aromatic ring, wherein thelink formed by R² and R³ is optionally substituted by one or moresubstituents selected from Z³ and —C₁₋₉alkyl optionally substituted byone or more Z⁴;each Y¹ independently represents halogen, —CN, —C(O)R^(a),—C(O)N(R^(b))R^(c), —C(O)OR^(d), —N(R^(e))R^(f), —N(R^(g))C(O)R^(h),—N(R^(i))C(O)OR^(j), —N(R^(k))C(O)N(R^(l))R^(m), —NO₂,—N(R^(n))S(O)₂R^(o), —OR^(p), —OC(O)R^(q), —OS(O)₂R^(r), —S(O)_(m)R^(s),—S(O)₂N(R^(t))R^(u), heterocycloalkyl optionally substituted by one ormore substituents selected from W², aryl optionally substituted by oneor more substituents selected from W³ or heteroaryl optionallysubstituted by one or more substituents selected from W³;Y^(1a) represents halogen, —CN, —C(O)R^(a), —C(O)N(R^(b))R^(c),—C(O)OR^(d), —N(R^(e))R^(f), —N(R^(g))C(O)R^(h), —N(R^(i))C(O)OR^(j),—N(R^(k))C(O)N(R^(l))R^(m), —NO₂, —N(R^(n))S(O)₂R^(o), —OR^(px),—OC(O)R^(g), —OS(O)₂R^(r), —S(O)_(m)R^(s), —S(O)₂N(R^(t))R^(u),heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³ or heteroaryl optionally substituted byone or more substituents selected from W³;Y^(1b) represents halogen, —CN, —C(O)R^(a), —C(O)N(R^(b))R^(c),—C(O)OR^(d), —N(R^(e))R^(f), —N(R^(g))C(O)R^(h), —N(R^(i))C(O)OR^(j),—N(R^(k))C(O)N(R^(l))R^(m), —NO₂, —N(R^(n))S(O)₂R^(o), —OR^(p),—OC(O)R^(g), —OS(O)₂R^(r), —S(O)_(m)R^(s), —S(O)₂N(R^(t))R^(u),heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³ or heteroaryl optionally substituted byone or more substituents selected from W³;each R^(a), R^(b), R^(c), R^(d), R^(e), R^(g), R^(h), R^(i), R^(k),R^(l), R^(m), R^(n), R^(p), R^(s), R^(t) and R^(u) independentlyrepresents hydrogen, —C₁₋₆ alkyl optionally substituted by one or moresubstituents selected from W¹, heterocycloalkyl optionally substitutedby one or more substituents selected from W², aryl optionallysubstituted by one or more substituents selected from W³, or heteroaryloptionally substituted by one or more substituents selected from W³; orany two R^(b) and R^(c), R^(e) and R^(f), R^(l) and R^(m) and/or R^(t)and R^(u) are linked together to form, along with the nitrogen atom towhich they are attached, a 3- to 8-membered monocyclic or bicyclic ring,which ring optionally contains one or two further heteroatoms and whichring optionally is substituted by one or more substituents selected fromW², C₁₋₃alkyl optionally substituted by one or more substituentsselected from W¹, and ═O;each R^(f), R^(j), R^(o), R^(r) and R^(px) independently represents C₁₋₆alkyl optionally substituted by one or more substituents selected fromW¹, heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³ or heteroaryl optionally substituted byone or more substituents selected from W³;each Y² independently represents halogen, —CN, —C(O)R^(b1),—C(O)N(R^(c1))R^(d1), —C(O)OR^(e1), —N(R^(f1))R^(g1),—N(R^(h1))C(O)R^(i1), —N(R^(j1))C(O)OR^(k1),—N(R^(l1))C(O)N(R^(m1))R^(n1), —N(R^(o1))S(O)₂R^(p1), —OR^(q1),—OC(O)R^(r1), —OS(O)₂R^(s1), —S(O)_(m)R^(t1), —S(O)₂N(R^(u1))R^(v1),heterocycloalkyl optionally substituted by one or more substituentsselected from W¹, aryl optionally substituted by one or moresubstituents selected from W², heteroaryl optionally substituted by oneor more substituents selected from W², or ═O;each Y³ independently represents halogen, —R^(a1), —CN, —C(O)R^(b1),—C(O)N(R^(c1))R^(d1), —C(O)OR^(e1), —N(R^(f1))R^(g1),—N(R^(h1))C(O)R^(i1), —N(R^(j1))C(O)OR^(k1),—N(R^(l1))C(O)N(R^(m1))R^(n1), —N(R^(o1))S(O)₂R^(p1), —OR^(q1),—OC(O)R^(r1), —OS(O)₂R^(s1), —S(O)_(m)R^(t1), —S(O)₂N(R^(u1))R^(v1),heterocycloalkyl optionally substituted by one or more substituentsselected from W¹, aryl optionally substituted by one or moresubstituents selected from W², heteroaryl optionally substituted by oneor more substituents selected from W², or ═O;each R^(a1), R^(b1), R^(c1), R^(d1), R^(e1), R^(f1), R^(h1), R^(i1),R^(j1), R^(l1), R^(m1), R^(n1), R^(o1), R^(q1), R^(r1), R^(t1), R^(u1)and R^(v1) independently represents hydrogen, C₁₋₆ alkyl optionallysubstituted by one or more substituents selected from W¹,heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³, or heteroaryl optionally substituted byone or more substituents selected from W³; orany two R^(c1) and R^(d1), R^(f1) and R^(g1), R^(m1) and R^(n1) and/orR^(u1) and R^(v1) are linked together to form, along with the nitrogenatom to which they are attached, a 3- to 8-membered monocyclic orbicyclic ring, which ring optionally contains one or two heteroatoms andwhich ring optionally is substituted by one or more substituentsselected from W², C₁₋₃alkyl optionally substituted by one or moresubstituents selected from W¹, and ═O;each R^(g1), R^(k1), R^(p1) and R^(s1) independently represents —C₁₋₆alkyl optionally substituted by one or more substituents selected fromW¹, heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³, or heteroaryl optionally substituted byone or more substituents selected from W³;each Z¹ independently represents halogen, —CN, —C(O)R^(b2),—C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2),—N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl represented by

heteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or onesulfur atom and optionally substituted by one or more substituentsselected from W⁶, or ═O;each Z² and Z³ independently represents halogen, —R^(a2), —CN,—C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2),—N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶;each Z⁴ independently represents halogen, —CN, —C(O)R^(b2),—C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2),—N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, heteroaryl optionally substituted by oneor more substituents selected from W⁶, or ═O;each R^(a2), R^(b2), R^(c2), R^(d2), R^(e2), R^(f2), R^(h2), R^(i2),R^(j2), R^(l2), R^(m2), R^(n2), R^(o2), R^(q2), R^(r2), R^(t2), R^(u2)and R^(v2) independently represents hydrogen, C₁₋₆ alkyl optionallysubstituted by one or more substituents selected from W⁴,heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶; orany two R^(c2) and R^(d2), R^(f2) and R^(g2), R^(m2) and R^(n2) and/orR^(u2) and R^(v2) are linked together to form, along with the nitrogenatom to which they are attached, a 3- to 8-membered monocyclic orbicyclic ring, which ring optionally contains one or two heteroatoms andwhich ring optionally is substituted by one or more substituentsselected from W⁵, C₁₋₃alkyl optionally substituted by one or moresubstituents selected from W⁴), and ═O;each R^(g2), R^(k2), R^(p2) and R^(s2) independently represents C₁₋₆alkyl optionally substituted by one or more substituents selected fromW⁴, heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶; each W¹ and W⁴ independentlyrepresents halogen, —CN, —N(V)R^(g3), —N(R^(h3))C(O)R^(i3),—N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3),—N(R^(o3))S(O)₂R^(p3), —OR^(q3), —OC(O)R^(r3), —OS(O)₂R^(s3),—S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionallysubstituted by one or more substituents selected from G¹, aryloptionally substituted by one or more substituents selected from G²,heteroaryl optionally substituted by one or more substituents selectedfrom G², or ═O;each W², W³, W⁵ and W⁶ independently represents halogen, —R^(a3), —CN,—C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3),—N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², heteroaryl (optionally substituted by oneor more substituents selected from G², or ═O;each W⁷, W⁸, W⁹, W¹⁹ and W¹¹ independently represents hydrogen, halogen,—R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3),—N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², or heteroaryl optionally substituted byone or more substituents selected from G²;each R^(a3), R^(b3), R^(c3), R^(d3), R^(e3), R^(f3), R^(h3), R^(i3),R^(j3), R^(l3), R^(m3), R^(n3), R^(o3), R^(q3), R^(r3), R^(t3), R^(u3)and R^(v3) independently represents hydrogen or C₁₋₆ alkyl optionallysubstituted by one or more G³; orany two R^(c3) and R^(d3), R^(f3) and R^(g3), R^(m3) and R^(n3) and/orR^(u3) and R^(v3) are linked together to form, along with the nitrogenatom to which they are attached, a 4- to 6-membered ring, which ringoptionally contains one heteroatom and which ring optionally issubstituted by one or more G²;each R^(g3), R^(k3), R^(p3), R^(q3) and R^(s3) independently representsC₁₋₆ alkyl optionally substituted by one or more G³;each G¹ and G² independently represents halogen, —R^(a4), —CN,—C(O)R^(b4), —C(O)N(R^(c4))R^(d4), —C(O)OR^(e4), —N(R^(f4))R^(g4),—N(R^(h4))C(O)R^(i4), —N(R^(j4))C(O)OR^(k4),—N(R^(l4))C(O)N(R^(m4))R^(n4), —N(R^(o4))S(O)₂R^(p4), —OR^(q4),—OC(O)R^(r4), —OS(O)₂R^(s4), —S(O)_(m)R^(t4), —S(O)₂N(R^(u4))R^(v4), or═O;

-   -   G³ represents halogen, —CN, —C(O)R^(b4), —C(O)N(R^(c4))R^(d4),        —C(O)OR^(e4), —N(R^(f4))R^(g4), —N(R^(h4))C(O)R^(i4),        —N(R^(j4))C(O)OR^(k4), —N(R^(l4))C(O)N(R^(m4))R^(n4),        —N(R^(o4))S(O)₂R^(p4), —OR^(q4), —OC(O)R^(r4), —OS(O)₂R^(s4),        —S(O)_(m)R^(t4), —S(O)₂N(R^(u4))R^(v4), or ═O;        each R^(a4), R^(b4), R^(c4), R^(d4), R^(e4), R^(f4), R^(h4),        R^(i4), R^(j4), R^(l4), R^(m4), R^(n4), R^(o4), R^(q4), R^(r4),        R^(t4), R^(u4) and R^(v4) independently represents hydrogen or        C₁₋₆ alkyl optionally substituted by one or more —F; or        any two R^(c4) and R^(d4), R^(f4) and R^(g4), R^(m4) and R^(n4)        and/or R^(ua) and R^(v4) are linked together to form, along with        the nitrogen atom to which they are attached, a 3- to 6-membered        ring, which ring optionally substituted by one or more —F, —CH₃,        —CH₂CH₃, —CHF₂, —CF₃, —CH₂CF₃, or ═O;        each R^(g4), R^(k4), R^(p4) and R^(s4) independently represent        C₁₋₆ alkyl optionally substituted by one or more —F;        each m independently represents 0, 1 or 2;        provided that formula I does not represent

-   N⁴-cyclopropyl-6-(4-methoxy-2-methylphenyl)-2,4-pyrimidinediamine    or a pharmaceutically acceptable salt thereof;    which compounds may be referred to herein as “the compounds of the    invention”.

Pharmaceutically-acceptable salts include acid addition salts and baseaddition salts. Such salts may be formed by conventional means, forexample by reaction of a free acid or a free base form of a compound offormula I with one or more equivalents of an appropriate acid or base,optionally in a solvent, or in a medium in which the salt is insoluble,followed by removal of said solvent, or said medium, using standardtechniques (e.g. in vacuo, by freeze-drying or by filtration). Salts mayalso be prepared by exchanging a counter-ion of a compound of theinvention in the form of a salt with another counter-ion, for exampleusing a suitable ion exchange resin. For the avoidance of doubt,solvates are also included within the scope of the invention.

Compounds of the invention may contain double bonds and may thus existas E (entgegen) and Z (zusammen) geometric isomers about each individualdouble bond. All such isomers and mixtures thereof are included withinthe scope of the invention.

Compounds of the invention may also exhibit tautomerism. All tautomericforms and mixtures thereof are included within the scope of theinvention.

Compounds of the invention may also contain one or more asymmetriccarbon atoms and may therefore exhibit optical and/ordiastereoisomerism. Diastereoisomers may be separated using conventionaltechniques, e.g. chromatography or fractional crystallisation. Thevarious stereoisomers may be isolated by separation of a racemic orother mixture of the compounds using conventional, e.g. fractionalcrystallisation or HPLC, techniques. Alternatively the desired opticalisomers may be made by reaction of the appropriate optically activestarting materials under conditions which will not cause racemisation orepimerisation (i.e. a ‘chiral pool’ method), by reaction of theappropriate starting material with a ‘chiral auxiliary’ which cansubsequently be removed at a suitable stage, by derivatisation (i.e. aresolution, including a dynamic resolution), for example with ahomochiral acid followed by separation of the diastereomeric derivativesby conventional means such as chromatography, or by reaction with anappropriate chiral reagent or chiral catalyst all under conditions knownto the skilled person. All stereoisomers and mixtures thereof areincluded within the scope of the invention.

Unless otherwise specified, C_(1-q) alkyl groups (where q is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number (i.e. a minimum of two or three, as appropriate)of carbon atoms, be branched-chain, and/or cyclic (so forming aC_(3-q)-cycloalkyl group). When there is a sufficient number (i.e. aminimum of four) of carbon atoms, such groups may also be part cyclic.Such alkyl groups may also be saturated or, when there is a sufficientnumber (i.e. a minimum of two) of carbon atoms, be unsaturated (forming,for example, a C_(2-q) alkenyl or a C_(2-q) alkynyl group).

Unless otherwise specified, C_(1-q) alkylene groups (where q is theupper limit of the range) defined herein may (in a similar manner to thedefinition of C_(1-q) alkyl) be straight-chain or, when there is asufficient number (i.e. a minimum of two or three, as appropriate) ofcarbon atoms, be branched-chain, and/or cyclic (so forming aC_(3-q)-cycloalkylene group). When there is a sufficient number (i.e. aminimum of four) of carbon atoms, such groups may also be part cyclic.Such alkylene groups may also be saturated or, when there is asufficient number (i.e. a minimum of two) of carbon atoms, beunsaturated (forming, for example, a C_(2-q)alkenylene or aC_(2-q)alkynylene group). Particular alkylene groups that may bementioned include those that are straight-chained and saturated.

The term “halo”, when used herein, includes fluoro, chloro, bromo andiodo (for example, fluoro and chloro).

Heterocycloalkyl groups that may be mentioned include non-aromaticmonocyclic and bicyclic heterocycloalkyl groups (which groups mayfurther be bridged) in which at least one (e.g. one to four) of theatoms in the ring system is other than carbon (i.e. a heteroatom), andin which the total number of atoms in the ring system is between threeand twelve (e.g. between five and ten and, most preferably, betweenthree and eight, e.g. a 5- or 6-membered heterocycloalkyl group).Further, such heterocycloalkyl groups may be saturated or unsaturatedcontaining one or more double and/or triple bonds, forming for example aC_(2-q) (e.g. heterocycloalkenyl (where q is the upper limit of therange) or a C_(7-q) heterocycloalkynyl group. C_(2-q) heterocycloalkylgroups that may be mentioned include 7-azabicyclo-[2.2.1]heptanyl,6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl,8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl,dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl),dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyland 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl(including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl,7-oxabicyclo-[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl, oxetanyl,oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl,pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl,3-sulfolenyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyridyl(such as 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl),thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including1,3,5-trithianyl), tropanyl and the like. Substituents onheterocycloalkyl groups may, where appropriate, be located on any atomin the ring system including a heteroatom. Further, in the case wherethe substituent is another cyclic compound, then the cyclic compound maybe attached through a single atom on the heterocycloalkyl group, forminga so-called “spiro”-compound. The point of attachment ofheterocycloalkyl groups may be via any atom in the ring system including(where appropriate) a heteroatom (such as a nitrogen atom), or an atomon any fused carbocyclic ring that may be present as part of the ringsystem. Heterocycloalkyl groups may also be in the N- or S-oxidisedform. At each occurrence when mentioned herein, a heterocycloalkyl groupis preferably a 3- to 8-membered heterocycloalkyl group (e.g. a 5- or6-membered heterocycloalkyl group).

The term “aryl”, when used herein, includes C₆₋₁₄ (e.g. C₆₋₁₀ aromaticgroups. Such groups may be monocyclic or bicyclic and, when bicyclic, beeither wholly or partly aromatic. C₆₋₁₀ aryl groups that may bementioned include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl,and the like (e.g. phenyl, naphthyl and the like). For the avoidance ofdoubt, the point of attachment of substituents on aryl groups may be viaany carbon atom of the ring system.

The term “heteroaryl” (or heteroaromatic), when used herein, includes 5-to 10-membered heteroaromatic groups containing one or more heteroatomsselected from oxygen, nitrogen and/or sulfur. Such heteroaryl group maycomprise one, or two rings, of which at least one is aromatic.Substituents on heteroaryl/heteroaromatic groups may, where appropriate,be located on any atom in the ring system including a heteroatom. Thepoint of attachment of heteroaryl/heteroaromatic groups may be via anyatom in the ring system including (where appropriate) a heteroatom.Bicyclic heteroaryl/heteroaromatic groups may comprise a benzene ringfused to one or more further aromatic or non-aromatic heterocyclicrings, in which instances, the point of attachment of the polycyclicheteroaryl/heteroaromatic group may be via any ring including thebenzene ring or the heteroaryl/heteroaromatic or heterocycloalkyl ring.Examples of heteroaryl/heteroaromatic groups that may be mentionedinclude pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl,thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, pyrimidinyl,indolyl, azaindolyl, pyrazinyl, indazolyl, pyrimidinyl, quinolinyl,isoquinolinyl, benzofuranyl, benzothiophenyl, benzoimidazolyl,benzoxazolyl, benzothiazolyl and benzotriazolyl. The oxides ofheteroaryl/heteroaromatic groups are also embraced within the scope ofthe invention (e.g. the N-oxide). As stated above, heteroaryl includespolycyclic (e.g. bicyclic) groups in which one ring is aromatic (and theother may or may not be aromatic). Hence, other heteroaryl groups thatmay be mentioned include e.g. benzo[1,3]dioxolyl, benzo[1,4]dioxinyl,indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl,1,2,3,4-tetra-hydroquinolinyl and the like.

Heteroatoms that may be mentioned include phosphorus, silicon, boronand, preferably, oxygen, nitrogen and sulfur.

For the avoidance of doubt, in cases in which the identity of two ormore substituents in a compound of the invention may be the same, theactual identities of the respective substituents are not in any wayinterdependent.

For the avoidance of doubt, when R¹ is defined as

it is connected to the rest of formula I by the bond interrupted by thewiggly line, and formula I can thus be represented by

Likewise, when R³ is —C₁₋₁₂ alkyl substituted by Z¹, and Z¹ isrepresented by

then, if e.g. R³ is C₂alkyl, then formula I can be represented by

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature (or the most abundant one found in nature). Allisotopes of any particular atom or element as specified herein arecontemplated within the scope of the compounds of the invention. Hence,the compounds of the invention also include deuterated compounds, i.e.in which one or more hydrogen atoms are replaced by the hydrogen isotopedeuterium.

All individual features (e.g. preferred features) mentioned herein maybe taken in isolation or in combination with any other feature(including preferred features) mentioned herein (hence, preferredfeatures may be taken in conjunction with other preferred features, orindependently of them).

The skilled person will appreciate that compounds of the invention thatare the subject of this invention include those that are stable. Thatis, compounds of the invention include those that are sufficientlyrobust to survive isolation from e.g. a reaction mixture to a usefuldegree of purity.

Particular compounds of formula I that may be mentioned include those inwhich:

R² represents hydrogen or —C₁₋₁₂alkyl optionally substituted by one ormore Z¹; andR³ represents —C₁₋₁₂alkyl optionally substituted by one or more Z¹ orheterocycloalkyl optionally substituted by one or more Z².

For example, compounds of formula I that may be mentioned include thosein which R² represents methyl, or preferably, hydrogen and R³represents:

(a) —C₁₋₁₂alkyl (for example —C₁₋₆alkyl) optionally substituted by two,or preferably, one Z¹ or(b) —C₂₋₆alkyl optionally substituted by two, or preferably, one Z¹ orheterocycloalkyl optionally substituted by two, or preferably, one Z²;or(c) —C₁₋₂alkyl optionally substituted with one or more —F; or(d)

(e) —C₁₋₁₂alkyl (for example —C₁₋₆alkyl) substituted by heteroarylhaving 1 to 3 nitrogen atoms, one oxygen atom and/or one sulfur atom andwhich heteroaryl is optionally substituted by one or more substituentsselected from W³; or(f) a —C₃₋₆alkyl or a heterocycloalkyl selected from cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl,cyclopropylpropyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinylwherein the C₃₋₆alkyl is optionally substituted by two, or preferably,one Z¹ and the heterocycloalkyl is optionally substituted by two, orpreferably, one Z².

Particular compounds of formula I that may be mentioned include those inwhich: R² and R³ are linked together to form, along with the atoms towhich they are attached, a 5- to 8-membered (e.g. a 5- to 6 membered)non-aromatic ring, wherein the link formed by R² and R³ is optionallysubstituted by one or more substituents selected from Z³ or —C₁₋₉alkyloptionally substituted by one or more Z⁴.

For example, compounds of formula I that may be mentioned include thosein which R² and R³ are linked together to form, along with the atoms towhich they are attached, a 5- to 6-membered non-aromatic ring, whereinthe non-aromatic ring is:

-   (a) unsubstituted; or-   (b) substituted by one or more substituents selected from Z³; or-   (c) substituted by —C₁₋₉alkyl optionally substituted by one or more    Z⁴; or-   (d) substituted by one or more substituents selected from Z³ and    substituted by —C₁₋₉alkyl optionally substituted by one or more Z⁴.

Particular compounds of formula I that may be mentioned include those inwhich:

-   R¹ represents

Preferred compounds of formula I that may be mentioned include those inwhich E¹ represents Y^(1a) or —C₁₋₆alkyl optionally substituted by oneor more Y²; and at least one of E², E³ and E⁴ (preferably at least oneof E² and E⁴) represents Y^(1b) or —C₁₋₆alkyl optionally substituted byone or more Y².

Particular compounds of formula I that may be mentioned include those inwhich R¹ represents heteroaryl.

Preferred compounds of formula I where R¹ represents heteroaryl that maybe mentioned are those where R¹ represents benzofuranyl,benzothiophenyl, dihydrobenzofuranyl, indazolyl, indolyl, isoquinolinyl,isoxazolyl, pyridinyl, pyrrolyl and quinolinyl.

Particularly preferred compounds of formula I where R¹ representsheteroaryl that may be mentioned are those where R¹ representsbenzofuran-3-yl, benzothiophen-3-yl, dihydrobenzofuran-7-yl, indol-3-yl,indol-4-yl, indol-5-yl, isoquinolin-4-yl, isoxazol-4-yl, pyridin-3-yl,pyridin-4-yl, pyrrol-2-yl and quinolin-5-yl.

For example, compounds of formula I that may be mentioned include thosein which R¹ represents indolyl, e.g. indol-3-yl, indol-4-yl orindol-5-yl, where the indolyl is optionally substituted on the nitrogenwith —S(O)₂Ar^(x), where Ar^(x) is aryl or heteroaryl, preferablyoptionally substituted phenyl, e.g. unsubstituted phenyl or phenylsubstituted in the 4-position by —F, —Cl, —CH₃ or —CF₃.

Particular compounds of formula I that may be mentioned include those inwhich

R¹ is represented by

where:E³ and E⁴ represent hydrogen; andE¹ represents —F and E² represent —F, —Cl, —CH₃ or —CF₃; orE¹ represents —Cl and E² represents —F, —Cl, —CH₃ or —CF₃; orE¹ represents —CH₃ and E² represents —F, —Cl, —CH₃, —CF₃, —CN or—N(H)C(O)CH═CH₂; orE² and E⁴ represent hydrogen; andE¹ represents —F and E³ represents —F or phenyl; orE¹ represents —Cl and E³ represents —F or —Cl; orE¹ represents —CH₃ and E³ represents —Cl or —OCH₂phenyl; orE¹ represents —OCH₃ and E³ represents —F; orE² and E³ represent hydrogen; andE¹ represents —F and E⁴ represents —Cl, —CH₃ or —CN; orE¹ represents —Cl and E⁴ represent —F, —Cl, —CH₃, —CF₃ or —OCH₃; orE¹ represents —CH₃ and E⁴ represent —F, —Cl, —CH₃, —CF₃, —CN,—N(H)C(O)CH═CH₂ or —S(O)₂(4-morpholinyl); orE¹ represents —CF₃ and E⁴ represents —F or —CF₃; orE¹ represents —CN and E⁴ represents —Cl; orE¹ represents —OCH₃ and E⁴ represents —F, —Cl, Br, —CH₃, —CH(CH₃)₂,—C(CH₃)₃, —CN or —OCH₃; orE¹ and E⁴ represent hydrogen; andE² represents —F and E³ represents —F, —Cl, —OH or —OCH₃; orE² represents —Cl and E³ represents —F or —C(O)(4-morpholinyl); orE² represents —CH₃ and E³ represents —F or —OCH₃; orE¹ represents —OCH₃ and E³ represents —OH; orE¹ represents-CH₂OCH₃ and E³ represents (piperidin-4-yl)methoxy or((1-tertbutoxycarbonyl)piperidin-4-yl)methoxy; orE¹ and E³ represent hydrogen; andE² and E⁴ represent —F; orE² and E⁴ represent —CF₃; orE⁴ represents hydrogen; andE¹, E² and E³ represent —F; orE¹ and E² represent —Cl and E³ represents —Cl, —OH or —OCH₃; orE¹ and E² represent —CH₃ and E³ represents —F or —OCH₃; orE² and E³ represent —Cl and E¹ represents —CH₃; orE² represents hydrogen; andE¹, E³ and E⁴ represent —F; orE³ and E⁴ represent —Cl and E¹ represents —CH₃; orE¹ and E⁴ represent —Cl and E¹ represents —OCH₃; orE¹ and E⁴ represent —CH₃ and E³ represents —F, —CH₃ or —OCH₃; orE¹ represents —F, E³ represents —CH₃ and E⁴ represents —Cl; orE¹ represents —Cl, E³ represents —F and E⁴ represents —CH₃; orE¹ represents —Cl, E³ represents —CH₃ and E⁴ represents —F; orE¹ and E⁴ represent —CH₃ and E³ represents —F; orE¹ represents —CH₃, E⁴ represents —Cl and E³ represents —CF₃ or —OCH₃;orE¹ represents hydrogen; andE² and E⁴ represent —CH₃ and E³ represents —OH; orE³ represents hydrogen; andE¹ and E² represent —Cl and E⁴ represents —CH₃.

Preferred particular compounds of formula I that may be mentionedinclude those in which R¹ is represented by

where:E³ and E⁴ represent hydrogen; andE¹ represents —F and E² represents —F, —Cl, or —CF₃; orE¹ represents —Cl and E² represents —Cl, —CH₃ or —CF₃; orE¹ represents —CH₃ and E² represents —Cl, —CH₃, —CN or —N(H)C(O)CH═CH₂;orE² and E⁴ represent hydrogen; andE¹ and E³ represent —F; orE¹ represents —Cl and E³ represents —F or —Cl; orE¹ represents —CH₃ and E³ represents —Cl; orE² and E³ represent hydrogen; andE¹ represents —F and E⁴ represents —Cl, —CH₃ or —CN; orE¹ represents —Cl and E⁴ represents —F, —Cl, —CH₃ or —CF₃; orE¹ represents —CH₃ and E⁴ represent, —Cl, —CH₃, —CF₃, —CN or—N(H)C(O)CH═CH; orE¹ represents —CF₃ and E⁴ represents —F or —CF₃; orE¹ represents —CN and E⁴ represents —Cl; orE⁴ represents hydrogen; andE¹, E² and E³ represent —F; orE¹ and E² represent —CH₃ and E³ represents —F₃; orE² and E³ represent —Cl and E¹ represents —CH₃; orE² represents hydrogen; andE¹, E³ and E⁴ represent —F; orE³ and E⁴ represent —Cl and E¹ represents —CH₃; orE¹ and E⁴ represent —CH₃ and E³ represents —F or —CH₃; orE¹ represents —F, E³ represents —CH₃ and E⁴ represents —Cl; orE¹ represents —Cl, E³ represents —F and E⁴ represents —CH₃; orE¹ represents —Cl, E³ represents —CH₃ and E⁴ represents —F; orE¹ and E⁴ represent —CH₃ and E³ represents —F; orE¹ represents —CH₃, E³ represents —CF₃ and E⁴ represents —Cl; orE¹ represents hydrogen; andE² and E⁴ represent —CH₃ and E³ represents —OH; orE³ represents hydrogen; andE¹ and E² represent —Cl and E⁴ represents —CH₃.

Preferred compounds of formula I that may be mentioned include those inwhich:

(a) Z¹ is not present or is selected from —F, —CN, —C(O)R^(b2),—C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2),—N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionallysubstituted by one or more substituents selected from W⁵, arylrepresented by

orheteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or onesulfur atom and optionally substituted by one or more substituentsselected from W⁶; or(b) Z² is not present or is selected from —F, —R^(a2),—C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2),—N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2),—N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶.

Other preferred compounds of formula I that may be mentioned includethose in which:

(a) Z³ is not present or is selected from —F, —R^(a2),—C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2),—N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2),—N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶; and/or

(b) Z⁴ is not present or is selected from —F, —C(O)N(R^(c2))R^(d2),—N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionallysubstituted by one or more substituents selected from W⁵, aryloptionally substituted by one or more substituents selected from W⁶, orheteroaryl optionally substituted by one or more substituents selectedfrom VV.

Particularly preferred compounds of formula I that may be mentionedinclude those in which Z¹ represents —F, —CN, —C(O)NH₂,—C(O)N(R^(c2))R^(d2), —C(O)-(4-morpholinyl), —C(O)OEt, —N(H)C(O)Me,—N(H)C(O)R^(i2), —N(H)C(O)CH₂NMe₂, —N(H)C(O)OCMe₃, —N(H)C(O)OCH₂Ph,—N(Me)C(O)OCMe₃, —N(H)C(O)N(H)Me, —N(H)C(O)N(H)CHMe₂, —N(H)S(O)₂Me,—OMe, —OCF₃ and —OEt.

Preferred compounds of formula I where Z¹ represents heterocycloalkylthat may be mentioned are those where Z¹ represents dihydropyridinyl,imidazolinyl, morpholinyl, oxanyl, piperazinyl, piperidinyl,pyrrolidinyl and quinuclidinyl, wherein the heterocycloalkyl isoptionally substituted by one or more substituents selected from W⁵.

Preferred compounds of formula I where Z¹ represents

that may be mentioned are those where each W⁷, W¹⁰ and W¹¹ independentlyrepresents hydrogen, halogen, —R^(a3) or —CN; andone of W⁸ and W⁹ represents hydrogen, halogen, —R^(a3) or —CN and theother represents halogen, —R^(a3), —CN, —C(O)R^(b3),—C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3),—N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², or heteroaryl optionally substituted byone or more substituents selected from G².

Particularly preferred compounds of formula I where Z¹ represents

that may be mentioned are those where each W⁷, W¹⁰ and W¹¹ independentlyrepresents —F, —Cl, —CH₃, —CF₃, or more preferably, hydrogen; and one ofW⁸ and W⁹ (preferably W⁸) represents —F, —Cl, —CH₃, —CF₃, or morepreferably, hydrogen, and the other (preferably W⁹) represents halogen,—R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3),—N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², or heteroaryl optionally substituted byone or more substituents selected from G².

For example, particular compounds of formula I that may be mentionedinclude those wherein:

(a) W⁸, W⁹, W¹⁰ and W¹¹ represents hydrogen and W⁷ represents —Cl or—S(O)₂CH₃; or(b) W⁷, W⁹, W¹⁰ and W¹¹ represents hydrogen and W⁸ represents —F, —Br,—CN, —N(H)C(O)CH₃, —OCH₃ or —S(O)₂CH₃; or(a) W⁷, W¹⁰ and W¹¹ represents hydrogen and:

-   -   W⁸ and W⁹ represents —F or —Cl; or    -   (ii) W⁸ represents —F and W⁹ represents —CH₃.

More particularly preferred compounds of formula I where Z¹ represents

that may be mentioned are those where W⁷, W⁸, W¹⁰ and W¹¹ are hydrogenand W⁹ represents halogen, —R^(a3), —CN, —C(O)R^(b3),—C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3),—N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x),—S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionallysubstituted by one or more substituents selected from G¹, aryloptionally substituted by one or more substituents selected from G², orheteroaryl optionally substituted by one or more substituents selectedfrom G².

For example, more particularly preferred compounds of formula I that maybe mentioned are those where W⁷, W⁸, W¹⁰ and W¹¹ are hydrogen and W⁹represents —F, —Cl, —CH₃, cyclopropyl, —CF₃, —CN, —NH₂, —N(CH₃)₂,—N(H)C(O)CH₃, —N(H)C(O)OC(CH₃)₃, —SO₂CH₃, —SO₂NH₂, —S(O)₂N(CH₃)₂,—S(O)₂-4-morpholinyl, 4-methylpiperazin-1-yl,4-methylpiperidin-1-ylmethyl and 1,2,3-thiadiazol-4-yl.

Preferred compounds of formula I where Z¹ represents heteroaryl that maybe mentioned are those where Z¹ represents benzimidazolyl,benzodioxinyl, benzoxazolyl, furanyl, imidazolyl, imidazopyridinyl,indolyl, isoquinolinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridyl, pyrrolopyridinyl, quinolinyl, thiazolyl, thiophenyl andtriazolyl, wherein the heteroaryl is optionally substituted by one ormore substituents selected from W⁶.

Particularly preferred compounds of formula I where Z¹ representsheteroaryl that may be mentioned are those where Z¹ representsbenzimidazol-2-yl, 1,4-benzodioxin-2-yl, benzoxazol-2-yl, furan-2-yl,imidazol-1-yl, imidazol-4-yl, imidazo-[1,2-a]pyridin-2-yl, indol-3-yl,indol-5-yl, isoquinolin-4-yl, 1,3,4-oxadiazol-2-yl, 1,2-oxazol-4-yl,pyrazin-3-yl, pyrazol-1-yl, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 5H,6H,7H-pyrrolo[3,4-b]pyridin-5-yl, thiazol-5-yl,thiophen-2-yl, 1,2,3-triazol-4-yl and 1,2,4-triazol-3-yl, wherein theheteroaryl is optionally substituted by one or more substituentsselected from W⁶.

More particularly preferred compounds of formula I that may be mentionedare those where WP represents —F, —Cl, —Br, —CH₃, cyclopropyl, —CF₃,—CN, —NH₂, —N(CH₃)₂, —SO₂CH₃, —SO₂NH₂ and —SO)₂N(CH₃)₂.

In one embodiment, the compound according to the invention is selectedfrom the compounds of Examples 1-454

As discussed hereinbefore, compounds of the invention are indicated aspharmaceuticals. According to a further aspect of the invention there isprovided a compound of the invention, as hereinbefore defined, for useas a pharmaceutical.

In another aspect of the invention the use of a compound of theinvention, as hereinbefore defined, is provided for the manufacture of amedicament for the treatment of cancer.

Although compounds of the invention may possess pharmacological activityas such, certain pharmaceutically-acceptable (e.g. “protected”)derivatives of compounds of the invention may exist or be prepared whichmay not possess such activity, but may be administered parenterally ororally and thereafter be metabolised in the body to form compounds ofthe invention. Such compounds (which may possess some pharmacologicalactivity, provided that such activity is appreciably lower than that ofthe “active” compounds to which they are metabolised) may therefore bedescribed as “prodrugs” of compounds of the invention.

By “prodrug of a compound of the invention”, we include compounds thatform a compound of the invention, in an experimentally-detectableamount, within a predetermined time, following enteral or parenteraladministration (e.g. oral or parenteral administration). All prodrugs ofthe compounds of the invention are included within the scope of theinvention.

Furthermore, certain compounds of the invention may possess no orminimal pharmacological activity as such, but may be administeredparenterally or orally, and thereafter be metabolised in the body toform compounds of the invention that possess pharmacological activity assuch. Such compounds (which also includes compounds that may possesssome pharmacological activity, but that activity is appreciably lowerthan that of the “active” compounds of the invention to which they aremetabolised), may also be described as “prodrugs”.

Thus, the compounds of the invention are useful because they possesspharmacological activity, and/or are metabolised in the body followingoral or parenteral administration to form compounds, which possesspharmacological activity.

It is stated herein that the compounds of the invention may be useful inthe treatment of cancer. For the purposes of this specification, and forthe avoidance of doubt, the term “treatment” includes treatment per se,prevention and prophylaxis.

In an alternative embodiment, compounds of the invention may be usefulin the the treatment of cancer.

Preferably the cancer is selected from the group comprising: Soft TissueCancers: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung:bronchogenic carcinoma (squamous cell, undifferentiated small cell,undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar)carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoushamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cellcarcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach(carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma,insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), smallbowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma [pinealoma], glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma],fallopian tubes (carcinoma); Hematologic: blood and bone marrow (myeloidleukemia [acute and chronic], acute lymphoblastic leukemia, chroniclymphocytic leukemia, myeloproliferative diseases, multiple myeloma,myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma[malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma,squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi,lipoma, angioma, dermatofibroma, keloids; neurofibromatosis and Adrenalglands: neuroblastoma. The term “cancerous cell” as provided herein,includes a cell afflicted by any one of the above identified conditions.

In certain embodiments of the present invention, the cancer is a solidtumor cancer.

In certain embodiments of the present invention, the cancer is selectedfrom pancreatic cancer, ovarian cancer and colorectal cancer.

In certain embodiments of the present invention, the cancer is selectedfrom colorectal cancer (including Ras mutations), small cell lungcancer, non-small cell lung cancer, and glioma.

In certain embodiments of the present invention, the cancer is selectedfrom non-small cell lung cancer, ovarian cancer, metastatic breastcancer, pancreatic cancer, hepatobiliary cancer (includinghepatocellular cancer, bile duct cancer and cholangiocarcinoma), andgastric cancer.

In certain embodiments of the present invention, the cancer is selectedfrom colorectal cancer (including Ras mutations), small cell lungcancer, non-small cell lung cancer, ovarian cancer, hepatobiliary cancer(including hepatocellular cancer, bile duct cancer andcholangiocarcinoma), gastric cancer, testicular cancer, and head andneck squamous cell carcinoma.

In certain embodiments of the present invention, the cancer is selectedfrom leukemia (including acute myeloid leukemia, acute lymphoblasticleukemia, chronic myeloid leukemia, and chronic lymphoid leukemia),lymphoma (including mantle cell lymphoma, Hodgkin's lymphoma andnon-Hodgkin's lymphoma), and prostate cancer

Compounds of the invention will normally be administered orally,intravenously, subcutaneously, buccally, rectally, dermally, nasally,tracheally, bronchially, sublingually, intranasally, topically, by anyother parenteral route or via inhalation, in a pharmaceuticallyacceptable dosage form.

Compounds of the invention may be administered alone, but are preferablyadministered by way of known pharmaceutical compositions/formulations,including tablets, capsules or elixirs for oral administration,suppositories for rectal administration, sterile solutions orsuspensions for parenteral or intramuscular administration, and thelike.

Compounds of the invention (i.e. compounds that inhibit MTH1) may beadministered in the form of tablets or capsules, e.g., time-releasecapsules that are taken orally. Alternatively, the compounds of theinvention may be in a liquid form and may be taken orally or byinjection. The compounds of the invention may also be in the form ofsuppositories, or, creams, gels, and foams e.g. that can be applied tothe skin. In addition, they may be in the form of an inhalant that isapplied nasally.

Such compositions/formulations may be prepared in accordance withstandard and/or accepted pharmaceutical practice.

According to a further aspect of the invention there is thus provided apharmaceutical composition/formulation including a compound of theinvention, as hereinbefore defined, optionally in admixture with apharmaceutically acceptable adjuvant, diluent and/or carrier. Suchcompositions/formulations may be of use in the treatment, preventionand/or prophylaxis of cancer and diseases which benefit by inhibition ofMTH1.

Depending on e.g. potency and physical characteristics of the compoundof the invention (i.e. active ingredient), pharmaceutical formulationsthat may be mentioned include those in which the active ingredient ispresent in at least 1% (or at least 10%, at least 30% or at least 50%)by weight. That is, the ratio of active ingredient to the othercomponents (i.e. the addition of adjuvant, diluent and carrier) of thepharmaceutical composition is at least 1:99 (or at least 10:90, at least30:70 or at least 50:50) by weight.

The invention further provides a process for the preparation of apharmaceutical formulation, as hereinbefore defined, which processcomprises bringing into association a compound of the invention, ashereinbefore defined, or a pharmaceutically acceptable salt thereof witha pharmaceutically-acceptable adjuvant, diluent or carrier.

In yet another aspect the present invention provides methods for thetreatment of cancer comprising administering a therapeutically effectiveamount of a compound of the invention to a subject (e.g. patient) inneed of such treatment.

“Patients” include mammalian (including human) patients.

The term “effective amount” refers to an amount of a compound, whichconfers a therapeutic effect on the treated patient. The effect may beobjective (i.e. measurable by some test or marker) or subjective (i.e.the subject gives an indication of or feels an effect).

Compounds of the invention may also be combined with other therapeuticagents that are useful in the treatment of cancer.

According to a further aspect of the invention, there is provided acombination product comprising:

(A) a compound of the invention, as hereinbefore defined; and(B) another therapeutic agent that is useful in the in the treatment ofcancer, wherein each of components (A) and (B) is formulated inadmixture with a pharmaceutically-acceptable adjuvant, diluent orcarrier.

Such combination products provide for the administration of a compoundof the invention in conjunction with the other therapeutic agent, andmay thus be presented either as separate formulations, wherein at leastone of those formulations comprises a compound of the invention, and atleast one comprises the other therapeutic agent, or may be presented(i.e. formulated) as a combined preparation (i.e. presented as a singleformulation including a compound of the invention and the othertherapeutic agent).

Thus, there is further provided:

(1) a pharmaceutical formulation including a compound of the invention,as hereinbefore defined, another therapeutic agent that is useful in thetreatment of cancer, and a pharmaceutically-acceptable adjuvant, diluentor carrier; and(2) a kit of parts comprising components:

-   -   (a) a pharmaceutical formulation including a compound of the        invention, as hereinbefore defined, in admixture with a        pharmaceutically-acceptable adjuvant, diluent or carrier; and    -   (b) a pharmaceutical formulation including another therapeutic        agent that is useful in the treatment of cancer in admixture        with a pharmaceutically-acceptable adjuvant, diluent or carrier,        which components (a) and (b) are each provided in a form that is        suitable for administration in conjunction with the other.

The invention further provides a process for the preparation of acombination product as hereinbefore defined, which process comprisesbringing into association a compound of the invention, as hereinbeforedefined, or a pharmaceutically acceptable salt thereof with the othertherapeutic agent that is useful in the treatment of cancer, and atleast one pharmaceutically-acceptable adjuvant, diluent or carrier.

By “bringing into association”, we mean that the two components arerendered suitable for administration in conjunction with each other.

Thus, in relation to the process for the preparation of a kit of partsas hereinbefore defined, by bringing the two components “intoassociation with” each other, we include that the two components of thekit of parts may be:

(i) provided as separate formulations (i.e. independently of oneanother), which are subsequently brought together for use in conjunctionwith each other in combination therapy; or(ii) packaged and presented together as separate components of a“combination pack” for use in conjunction with each other in combinationtherapy.

Compounds of the invention may be administered at varying doses. Oral,pulmonary and topical dosages (and subcutaneous dosages, although thesedosages may be relatively lower) may range from between about 0.01 mg/kgof body weight per day (mg/kg/day) to about 100 mg/kg/day, preferablyabout 0.01 to about 10 mg/kg/day, and more preferably about 0.1 to about5.0 mg/kg/day. For e.g. oral administration, the compositions typicallycontain between about 0.01 mg to about 2000 mg, for example betweenabout 0.1 mg to about 500 mg, or between 1 mg to about 100 mg, of theactive ingredient. Intravenously, the most preferred doses will rangefrom about 0.001 to about 10 mg/kg/hour during constant rate infusion.Advantageously, compounds may be administered in a single daily dose, orthe total daily dosage may be administered in divided doses of two,three or four times daily.

In any event, the physician, or the skilled person, will be able todetermine the actual dosage which will be most suitable for anindividual patient, which is likely to vary with the route ofadministration, the type and severity of the condition that is to betreated, as well as the species, age, weight, sex, renal function,hepatic function and response of the particular patient to be treated.The above-mentioned dosages are exemplary of the average case; therecan, of course, be individual instances where higher or lower dosageranges are merited, and such are within the scope of this invention.

Compounds of the invention may also have the advantage that they may bemore efficacious than, be less toxic than, be longer acting than, bemore potent than, produce fewer side effects than, be more easilyabsorbed than, and/or have a better pharmacokinetic profile (e.g. higheroral bioavailability and/or lower clearance) than, and/or have otheruseful pharmacological, physical, or chemical properties over, compoundsknown in the prior art, whether for use in the above-stated indicationsor otherwise. In particular, compounds of the invention may have theadvantage that they are more efficacious and/or exhibit advantageousproperties in vivo.

It is contemplated that any method or composition described herein canbe implemented with respect to any other method or composition describedherein.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention pertains.

EXAMPLES

The invention is illustrated by way of the following examples, in whichthe following abbreviations may be employed.

-   aq aqueous-   DMF dimethylformamide-   DMSO dimethyl sulfoxide-   EtOAc ethyl acetate-   EtOH ethanol-   MeOH methanol-   MeCN acetonitrile-   Pd—C palladium on carbon-   sat. saturated-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   min. minutes-   h. hours-   Hunigs base N,N-diisopropylethylamine-   DCM dichloromethane-   n-BuOH butan-1-ol-   iPrOH propan-2-ol-   NEt₃ triethylamine-   Boc tert-butoxycarbonyl-   HATU    (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo-[4,5-b]pyridinium    3-oxid hexafluorophosphate-   NMP N-methylpyrrolidine-   LCMS liquid-chromatography electrospray mass spectroscopy-   NMR nuclear magnetic resonance-   NCS N-chlorosuccinimide-   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium (0)-   B(OMe)₃ trimethylborate-   n-BuLi n-butyl lithium-   MeI iodomethane-   NaOMe sodium methoxide-   CHCl₃ chloroform-   MgSO₄ anhydrous magnesium sulphate-   K₂CO₃ anhydrous potassium carbonate-   NH₄OH ammonium hydroxide-   Ac₂O acetic anhydride-   POCl₃ phosphorus oxychloride

Starting materials and chemical reagents specified in the synthesesdescribed below are commercially available, e.g. from Sigma-Aldrich,Fine Chemicals Combi-Blocks and other vendors.

In the event that there is a discrepancy between nomenclature and anycompounds depicted graphically, then it is the latter that presides(unless contradicted by any experimental details that may be given orunless it is clear from the context). Final compounds were named usingMarvin software version 6.1.

Purification of compounds may be carried out using silica gel columnchromatography or preparative reverse phase HPLC (ACE column, acidicgradients with MeCN—H₂O containing 0.1% TFA or XBridge column, basicgradients using MeCN—H₂O containing ammonium bicarbonate) to give theproducts as their free bases or trifluoroacetic acid salts.

Intermediate 1 (7-chloro-2H-1,3-benzodioxol-5-yl)boronic acid

Step 1: 6-bromo-4-chloro-2H-1,3-benzodioxole

To a solution of 5-bromo-2H-1,3-benzodioxole (60 μL, 0.50 mmol, 1 eq.)in acetonitrile (1 mL) was added 1-chloropyrrolidine-2,5-dione (73 mg,0.55 mmol, 1.1 eq.). The reaction was stirred overnight at roomtemperature. After completion of the reaction, the reaction mixture wasconcentrated and purified by column chromatography (Heptane/EtOAc100%→5:1) to afford the desired product as a colourless solid (104 mg,89%). LCMS [M+H]⁺ 234; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.05 (1H, s), 6.93(1H, s), 2.78 (2H, s).

Step 2: (7-chloro-2H-1,3-benzodioxol-5-yl)boronic acid

To a solution of 6-bromo-4-chloro-2H-1,3-benzodioxole (104 mg, 0.44mmol, 1 eq.) in THF (5.8 mL) was added, at −78° C., n-BuLi (2.5 M inhexanes, 265 μL, 0.66 mmol, 1.5 eq.). The reaction mixture was stirredat this temperature for 30 min, before addition of B(OMe)₃ (248 μL, 2.21mmol, 5 eq.). The reaction was slowly allowed to warm up to rt, 2N HClwas added, and stirring was continued for 1 h. The reaction mixture wasextracted with EtOAc, and the organic layer was dried over MgSO₄ andevaporated under reduced pressure. The crude product was purified bycolumn chromatography (Pentane/EtOAc 100%→3:1) to afford the desiredproduct as a white solid (22 mg, 25%). LCMS [M+H]⁺ 201; ¹H NMR (400 MHz,DMSO-d₆) δ_(H) 7.34 (1H, s), 6.81 (1H, s), 5.99 (2H, s).

Intermediate 22,3-dichloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

To a solution of 4-bromo-2,3-dichlorophenol (250 mg, 1.03 mmol, 1 eq.)in THF (10 mL) was added, at −78° C., n-BuLi (2.5 M in hexanes, 1.25 mL,3.10 mmol, 3 eq.). The reaction mixture was stirred at this temperaturefor 30 min, before addition of2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (316 μL, 1.55 mmol,1.5 eq.). The reaction was slowly allowed to warm up to rt, 2N HCl wasadded, and stirring was continued for 1 h. The reaction mixture wasextracted with EtOAc, and the organic layer was dried over MgSO₄ andevaporated under reduced pressure. The crude product was purified bycolumn chromatography (Pentane/EtOAc 100%→4:1) to afford the desiredproduct as a white solid (102 mg, 34%). LCMS [M+H]⁺ 289; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.47 (1H, d, J=8.1 Hz), 6.85 (1H, d, J=8.1 Hz), 1.36(12H, s).

Intermediate 3 (2,3-dichloro-4-methoxyphenyl)boronic acid

Step 1: 4-Bromo-2,3-dichlorophenol

To a solution of 2,3-dichlorophenol (1.0 g, 6.13 mmol, 1 eq.) in DCM (4mL) was added, at 0° C., bromine (348 μL, 6.75 mmol, 1.1 eq.) over 15min. The reaction was allowed to warm up to rt over 12 hours. NMR showedunreacted starting material, bromine (0.33 eq.) was added at 0° C. andthe reaction was allowed to warm up to rt over 12 hours. The reactionwas stopped by addition of Na₂S₂O₃, the organic layer was washed withbrine, dried with MgSO₄ and concentrated under reduced pressure. Thecrude product was purified by column chromatography (Pentane/EtOAc100%→25:1) to afford the desired product as a white solid (685 mg, 46%).LCMS [M+H]⁺ 239; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 10.98 (1H, s), 7.54(1H, d, J=8.8 Hz), 6.91 (1H, d, J=8.8 Hz).

Step 2: 1-Bromo-2,3-dichloro-4-methoxybenzene

To a solution of 4-bromo-2,3-dichlorophenol (200 mg, 0.83 mmol, 1 eq.)in DMF (3 mL) was added Cs₂CO₃ (538 mg, 1.65 mmol, 2 eq.) followed byiodomethane (208 μL, 3.3 mmol, 4 eq.). The reaction mixture was stirredat 70° C. for 3 h. The reaction was stopped by addition of H₂O,extracted with DCM, dried with MgSO₄ and concentrated under reducedpressure. The crude product was purified by column chromatography(Pentane/EtOAc 100%→20:1) to afford the desired product as a white solid(190 mg, 89%). LCMS [M+H]⁺ 256; ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.47 (1H,d, J=9.0 Hz), 6.73 (1H, d, J=8.8 Hz), 3.88 (3H, s).

Step 3: (2,3-dichloro-4-methoxyphenyl)boronic acid

To a solution of 1-bromo-2,3-dichloro-4-methoxybenzene (100 mg, 0.39mmol, 1 eq.) in THF (5 mL) was added, at −78° C., n-BuLi (2.5 M inhexanes, 234 μL, 0.59 mmol, 1.5 eq.). The reaction mixture was stirredat this temperature for 30 min, before addition of B(OMe)₃ (218 μL, 1.95mmol, 5 eq.). The reaction was slowly allowed to warm up to rt, 2N HClwas added, and stirring was continued for 1 h. The reaction mixture wasextracted with EtOAc, and the organic layer was dried over MgSO₄ andevaporated under reduced pressure. The crude product was purified bycolumn chromatography (Pentane/EtOAc 100%→3:1) to afford the desiredproduct as a white solid (52 mg, 59%). LCMS [M+H]⁺ 221; ¹H NMR (400 MHz,DMSO-d₆) δ_(H) 8.25 (1H, s), 7.35 (1H, d, J=8.1 Hz), 7.10 (1H, d, J=8.1Hz), 3.87 (3H, s).

Intermediate 4 (2,3-dichloro-5-methoxyphenyl)boronic acid

Step 1: 1-Bromo-3-chloro-5-methoxybenzene

1-Bromo-3-chloro-5-fluorobenzene (1 g, 4.77 mmol, 1 eq.) was treated at0° C. with sodium methoxide (25% in MeOH, 1.2 mL, 5.71 mmol, 1.2 eq.).The reaction mixture was stirred at 100° C. for 3 h. The solution wasconcentrated under reduced pressure, the crude product was extractedwith DCM, washed with H₂O, brine, dried over MgSO₄ and concentrated. Theproduct was obtained as a white solid (747 mg, 71%). LCMS [M+H]⁺ 220; ¹HNMR (400 MHz, CD₃Cl) δ_(H) 7.09 (1H, t, J=1.7 Hz), 6.94-6.92 (1H, m),6.83-6.80 (1H, m), 3.77 (3H, s).

Step 2: 1-Bromo-2,3-dichloro-5-methoxybenzene

To a solution of 1-bromo-3-chloro-5-methoxybenzene (300 mg, 1.35 mmol, 1eq.) in DMF (5 mL) was added trichloro-1,3,5-triazinane-2,4,6-trione(115 mg, 0.49 mmol, 0.36 eq.) and the reaction was stirred at 50° C. for3 h. The reaction mixture was concentrated and the crude product waspurified by column chromatography (Heptane/EtOAc 100%→20:1) to affordthe desired product as a white solid (253 mg, 73%). LCMS [M+H]⁺ 254; ¹HNMR (400 MHz, CD₃Cl) δ_(H) 7.09 (1H, d, J=3.0 Hz), 6.97 (1H, d, J=3.0Hz), 3.77 (3H, s).

Step 3: (2,3-dichloro-5-methoxyphenyl)boronic acid

To a solution of 1-bromo-2,3-dichloro-5-methoxybenzene (87 mg, 0.34mmol, 1 eq.) in THF (4.5 mL) was added, at −78° C., n-BuLi (2.5 M inhexanes, 205 μL, 0.51 mmol, 1.5 eq.). The reaction mixture was stirredat this temperature for 30 min, before addition of B(OMe)₃ (191 μL, 1.70mmol, 5 eq.). The reaction was slowly allowed to warm up to rt, 2N HClwas added, and stirring was continued for 1 h. The reaction mixture wasextracted with EtOAc, and the organic layer was dried over MgSO₄ andevaporated under reduced pressure to afford the desired product as awhite solid (75 mg, 100%). LCMS [M+H]⁺ 221.

Intermediate 5 4-chloro-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-2-amine

Step 1: ethyl 2-ethoxy-3,4,5,6-tetrahydropyridine-3-carboxylate

To a solution of ethyl 2-oxopiperidine-3-carboxylate (1.5 g, 8.76 mmol,1 eq.) in DCM (6.5 mL) under N₂ was added a solution of triethyloxoniumtetrafluoroborate (2.0 g, 10.51 mmol, 1.2 eq.) in DCM (6.5 mL). Thereaction mixture was stirred at room temperature overnight. The solutionwas poured in water (5 mL) and allowed to stand for 30 min. The organiclayer was washed with NaHCO₃, H₂O, dried over Na₂SO₄ and concentratedunder reduced pressure to afford the desired product as a colourless oil(1.2 g, 66%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.15 (2H, q, J=7.2 Hz),4.00-3.98 (2H, m), 3.46-3.44 (2H, m), 3.18-3.16 (1H, m), 1.97-1.95 (2H,m), 1.68-1.66 (1H, m), 1.49-1.47 (1H, m), 1.25 (3H, t, J=7.1 Hz), 1.20(3H, t, J=7.0 Hz).

Step 2: 2-amino-3H,4H,5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-4-one

A solution of sodium ethoxide (21% in EtOH, 197 μL, 2.51 mmol, 2.5 eq.)was added to the mixture of ethyl2-ethoxy-3,4,5,6-tetrahydropyridine-3-carboxylate (200 mg, 1 mmol, 1eq.) and guanidine hydrochloride (96 mg, 1 mmol, 1 eq.) in EtOH (2 mL).The reaction mixture was stirred a reflux overnight. The solvent wereremoved under vacuum and the obtained solid was dried to afford thedesired product as a light yellow solid (116 mg, 70% yield). ¹H NMR (400MHz, CDCl₃) δ_(H) 9.89 (1H, br s), 6.18 (1H, br s), 6.10 (2H, br s),3.10-3.08 (2H, m), 2.20-2.18 (2H, m), 1.61-1.59 (2H, m).

Step 3: 4-chloro-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-2-amine

A mixture of 2-amino-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-oneand acetic anhydride was heated at reflux for 1 h until completion ofthe reaction as monitored by LCMS. The solvent was removed under reducedpressure and the obtained residue was treated withbenzyltriethylammonium chloride (547 mg, 2.4 mmol, 2 eq.) and POCl₃ (671μL, 7.2 mmol, 6 eq.) and heated at reflux for 1 h. After evaporation ofthe solvents, ice water was added to the residue and HCl (6N, 5.5 mL)was added. The reaction mixture was heated at 50° C. overnight. Afterevaporation of the solvents, the residue is diluted in EtOAc and washedwith NaHCO₃, brine and dried over Na₂SO₄. The combined organic layerswere then evaporated, and the crude product was purified by columnchromatography (DCM/MeOH 98/2 200 mL, 95/5 100 mL). The pure product wasobtained as a yellow powder (45 mg, 20%). LCMS [M+H]⁺ 185. ¹H NMR (400MHz, CDCl₃) δ_(H) 8.09-8.03 (1H, br s), 3.28-3.26 (2H, m), 2.53-2.51(2H, m), 1.81-1.79 (2H, m).

Intermediate 6 4-chloro-6-phenylpyrimidin-2-amine

A mixture of 2-amino-4,6-dichloropyrimidine (3 g, 18.29 mmol, 1 eq.),phenylboronic acid (2.45 g, 20.12 mmol, 1.1 eq.), K₂CO₃ (5.06 g, 36.6mmol, 2 eq.) and Pd(PPh₃)₄ (700 mg, 0.6 mmol, 0.03 eq.) in 1,4-dioxane(15 mL) and water (1 mL) was heated in a sealed tube at 95° C. for 12 h.The mixture was run through a plug of silica using EtOAc as eluent,concentrated and purified by column chromatography (1:4 EtOAc/pentane)to give the desired product as a white solid (2.2 g, 60%). LCMS [M+H]⁺206; ¹H NMR (400 MHz, CDCl₃) δ_(H) 8.27-8.20 (2H, m), 8.16-8.05 (3H, m),7.19 (2H, s), 6.76 (1H, s).

Intermediate 7 6-chloro-4-N-propylpyrimidine-2,4-diamine

A solution of 4,6-dichloropyrimidin-2-amine (820 mg, 5.0 mmol, 1 eq.) inEtOH (40 mL) was treated with propan-1-amine (5.0 ml). The reactionmixture was stirred at 85° C. for 48 h. The mixture was cooled,concentrated by evaporation then flash-chromatographed over silica toafford the product as a colorless solid (705 mg; 76%). LCMS [M+H]⁺ 187.

Intermediate 8 4-N-tert-butyl-6-chloropyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (820 mg, 5.0 mmol, 1 eq.)in n-BuOH (20 mL) was added tert-butylamine (365 mg, 5.0 mmol, 1 eq.)and Hünig's base (645 mg, 5.0 mmol, 1 eq.). The reaction mixture wasstirred overnight at 95° C. The mixture was cooled and some unreactedstarting material removed by filtration. The filtrate was concentratedand the residue flash-chromatographed over silica to afford the product(0.27 g; 27%). LCMS [M+H]⁺ 201.

Intermediate 9 6-chloro-4-N-(oxan-4-yl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (492 mg, 3.0 mmol, 1 eq.)in n-BuOH (20 mL) was added tetrahydro-2H-pyran-4-amine (303 mg, 3.0mmol, 1 eq.) and Hünig's base (387 mg, 3.0 mmol, 1 eq.). The reactionmixture was stirred overnight at 95° C. The mixture was cooled theprecipitated solid was collected and washed with water to give theproduct (0.42 g; 37%). LCMS [M+H]⁺ 229.

Intermediate 10 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (164 mg, 1.0 mmol, 1 eq.)in n-BuOH (5 mL) were added cyclopropanamine (80 μL, 1.1 mmol, 1.1 eq.)and Hünig's base (260 μL, 1.5 mmol, 1.5 eq.). The reaction mixture wasstirred overnight at 95° C. The solvent was removed in vacuo. The crudeproduct was diluted in EtOAc and washed with H₂O, brine, dried overMgSO₄ and concentrated to afford the desired product as an off-whitesolid (152 mg, 82%). LCMS [M+H]⁺ 185; ¹H NMR (400 MHz, DMSO-d₆) δ_(H)7.29 (1H, s), 6.38 (2H, s), 5.85 (1H, s), 3.52 (1H, s), 0.73-0.64 (2H,m), 0.53-0.35 (2H, m).

Intermediate 11 6-chloro-4-N-(1-methoxybutan-2-yl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (500 mg, 3.1 mmol, 1 eq.)in n-BuOH (10 mL) were added 1-methoxybutan-2-amine (315 mg, 3.1 mmol, 1eq.) and Hünig's base (531 μL, 3.1 mmol, 1 eq.). The reaction mixturewas stirred overnight at 95° C. The solvent was removed in vacuo. Thecrude product was diluted in EtOAc and washed with H₂O, brine, driedover MgSO₄ and concentrated to afford the desired product as anoff-white solid (592 mg, 84%). LCMS [M+H]⁺ 231.

Intermediate 126-chloro-4-N-(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (164 mg, 1.00 mmol, 1eq.) in n-BuOH (5 mL) were added 2,2,2-trifluoroethanamine hydrochloride(149 mg, 1.1 mmol, 1.1 eq.) and NEt₃ (202 mg, 2.0 mmol, 2 eq.). Thereaction mixture was stirred overnight at 90° C. The solvent was removedin vacuo. The crude product was diluted in EtOAc and washed with H₂O,brine, dried over MgSO₄ and concentrated to afford the desired productas a yellow solid (59 mg, 26%). LCMS [M+H]⁺ 227.

Intermediate 13 6-chloro-4-N-(2,2-difluoroethyl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (164 mg, 1.00 mmol, 1eq.) in n-BuOH (5 mL) were added 2,2-difluoroethanamine hydrochloride(129 mg, 1.1 mmol, 1.1 eq.) and triethylamine (202 mg, 2.0 mmol, 2 eq.).The reaction mixture was stirred overnight at 90° C. The solvent wasremoved in vacuo. The crude product was diluted in EtOAc and washed withH₂O, brine, dried over MgSO₄ and concentrated to afford the desiredproduct as a yellow solid (80 mg, 38%). LCMS [M+H]⁺ 209.

Intermediate 14 6-chloro-4-N-(prop-2-en-1-yl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (500 mg, 3.04 mmol, 1eq.) in n-BuOH (10 mL) were added 2,2-difluoroethanamine hydrochloride(229 μL, 3.04 mmol, 1 eq.) and Hünig's base (584 μL, 3.35 mmol, 1.1eq.). The reaction mixture was stirred overnight at 95° C. The solventwas removed in vacuo. The crude product was diluted in EtOAc and washedwith H₂O, brine, dried over MgSO₄ and concentrated to afford the desiredproduct as a yellow solid (471 mg, 84%). LCMS [M+H]⁺ 185.

Intermediate 15 6-chloro-4-N-cyclopentylpyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (500 mg, 3.04 mmol, 1eq.) in n-BuOH (10 mL) were added cyclopentanamine (301 μL, 3.04 mmol, 1eq.) and Hünig's base (584 μL, 3.35 mmol, 1.1 eq.). The reaction mixturewas stirred overnight at 95° C. The solvent was removed in vacuo. Thecrude product was diluted in EtOAc and washed with H₂O, brine, driedover MgSO₄ and concentrated to afford the desired product as a brownfoam (620 mg, quantitative). LCMS [M+H]⁺ 213.

Intermediate 16 6-chloro-4-N-cyclobutylpyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (250 mg, 1.52 mmol, 1eq.) in n-BuOH (5 mL) were added cyclobutanamine (130 μL, 1.52 mmol, 1eq.) and Hünig's base (292 μL, 1.72 mmol, 1.1 eq.). The reaction mixturewas stirred overnight at 95° C. The solvent was removed in vacuo. Thecrude product was diluted in EtOAc and washed with H₂O, brine, driedover MgSO₄ and concentrated to afford the desired product as a whitesolid (248 mg, 80%). LCMS [M+H]⁺ 199.

Intermediate 17 6-iodo-4-N-methylpyrimidine-2,4-diamine

To a suspension of 6-Chloro-4-N-methylpyrimidine-2,4-diamine (1.5 g,9.43 mmol, 1 eq.) in acetone (6.2 mL) was added sodium iodide (7.9 g,52.8 mmol, 5.6 eq.) and hydrogen iodide (15 mL). The reaction mixturewas stirred at 60° C. for 12 h. The solid was filtered off, dissolved inEtOAc, washed with NaHCO₃, brine, dried over MgSO₄ and concentratedunder reduced pressure to afford the desired compound as an orange solid(1.7 g, 73%). LCMS [M+H]⁺ 251; ¹H NMR (400 MHz, CDCl₃) δ_(H) 6.27 (1H,s), 2.80 (3H, s).

Intermediate 18 6-chloro-4-N-(2-phenylethyl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (66 mg, 0.40 mmol, 1 eq.)in n-BuOH (2.5 mL) were added 2-phenylethanamine (75 μL, 0.60 mmol, 1.1eq.) and Hünig's base (100 μg, 0.60 mmol, 1.1 eq.). The reaction mixturewas stirred at 95° C. for 3 h. The solvent was removed in vacuo. Thecrude product was diluted in EtOAc and washed with H₂O, brine, driedover MgSO₄ and concentrated to afford the desired product as a yellowsolid (88 mg, 88%). LCMS [M+H]⁺ 249.

Intermediate 19 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine

A mixture of 2-amino-4,6-dichloropyrimidine (0.82 g, 5.0 mmol, 1 eq.),2,3-dimethylphenylboronic acid (0.75 g, 5.0 mmol, 1 eq.), K₂CO₃ (1.38 g,10.0 mmol, 2 eq.) and palladium tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol, 0.1 eq.) in 1,4-dioxane (20 mL) and water (5 mL)was heated in a sealed tube at 90° C. for 2.5 hours. The mixture was runthrough a plug of silica using EtOAc as eluent, concentrated andpurified by column chromatography (1:4 EtOAc/pentane) to give thedesired product as a white solid (0.76 g, 65%). LCMS [M+H]⁺ 234; ¹H NMR(400 MHz, CD₃OD) δ_(H) 7.21-7.29 (1H, m), 7.20-7.09 (2H, m), 6.70 (1H,s), 2.34 (3H, s), 2.23 (3H, s).

Intermediate 20 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine

A mixture of 4,6-dichloropyrimidin-2-amine (3.28 g, 20.0 mmol),methanamine (12.0 mL, 24.0 mmol; as a 2 M solution in methanol) andHünig's base in n-butanol (20 mL) was heated at 95° C. overnight. Themixture was concentrated and the crude was taken up in EtOAc (300 mL)and washed with water (3×150 mL). The organic layer was dried overMgSO4, filtered and concentrated to give the desired product as a buffsolid (2.90 g, 91%). LCMS [M+H]⁺ 159.

Intermediate 21 6-chloro-4-N-methylpyrimidine-2,4-diamine

A mixture of 4,6-dichloropyrimidin-2-amine (0.50 g, 3.05 mmol),(2,3-dichlorophenyl)boronic acid (0.64 g, 3.35 mmol), sodium carbonate(0.65 g, 6.10 mmol) and palladium tetrakis(triphenylphosphine)palladium(0) (0.088 g, 0.076 mmol) in 1,4-dioxane/water (30 mL; 4:1) was heatedin a sealed tube at 95° C. for 2 h. The reaction mixture was run througha plug of silica (EtOAc) and then concentrated. Purification by columnchromatography (1:4→1:3 EtOAc/hexane) afforded the desired product as awhite solid (0.26 g, 31%). LCMS [M+H]⁺ 274; ¹H NMR (400 MHz, DMSO-d₆)δ_(H) 6.89 (1H, s) 7.33 (2H, br s) 7.44-7.52 (2H, m) 7.71-7.81 (1H, m).

Intermediate 226-Chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine

A mixture of 4,6-dichloropyrimidin-2-amine (0.50 g, 3.05 mmol),2-(4-chlorophenyl)ethan-1-amine (0.56 mL, 3.96 mmol) and Hünig's base(0.80 mL, 4.57 mmol) in n-butanol (5 mL) was heated in a sealed tube at95° C. overnight. The mixture was concentrated and the crude was takenup in EtOAc (50 mL) and washed with water (3×40 mL). The organic layerwas dried over MgSO4, filtered and concentrated to give the desiredproduct as a buff solid (0.61 g, 71%). LCMS [M+H]⁺ 283.

Intermediate 231-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one

A mixture of 4,6-dichloropyrimidin-2-amine (1.64 g, 10.0 mmol),1-(3-aminopropyl)pyrrolidin-2-one (1.96 mL, 14.0 mmol) and Hünig's base(2.61 mL, 15.0 mmol) in n-butanol (20 mL) was heated in a sealed tube at110° C. overnight. The mixture was concentrated and the crude was takenup in EtOAc (300 mL) and washed with water (3×150 mL). The aqueouslayers were combined and extracted with EtOAc (2×200 mL). The combinedorganic layers were dried over MgSO4, filtered and concentrated to givethe desired product as a buff solid (1.63 g, 60%). LCMS [M+H]⁺ 270.

Intermediate 24 4-chloro-6-(3-chloro-2-methyl phenyl)pyrimidin-2-amine

A stirred mixture of 2-amino-4,6-dichloropyrimidine (0.50 g, 3.1 mmol),3-chloro-2-methylphenylboronic acid (0.57 g, 3.4 mmol), Na₂CO₃ (1.0 g,9.8 mmol), palladium tetrakis(triphenylphosphine)palladium (0) (88 mg,0.076 mmol), dioxane (22 mL) and water (8 mL) were heated in a sealedtube at 90° C. for 2 hours. The solvents were removed in vacuo and theremaining solid was added EtOAc (20 mL) and washed with water. Theorganic phase was dried over MgSO₄ and removed in vacuo. The crudematerial was purified by flash chromatography (1:4 EtOAc/petroleumether) to give the desired product as a white solid (365 mg, 47%). LCMS[M+H]⁺ 254; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 7.52-7.56 (1H, dd,J₁=6.5 Hz, J₂=2.5 Hz) 7.30-7.33 (2H, m) 7.26 (2H, s) 6.79 (1H, s) 2.32(3H, s).

Intermediate 254-{2-[(2-amino-6-chloropyrimidin-4-0amino]ethyl}benzene-1-sulfonamide

To a suspension of 4,6-dichloropyrimidin-2-amine (800 mg, 4.9 mmol) and4-(2-aminoethyl)benzenesulfonamide (980 mg, 4.9 mmol) in 2-propanol (10mL), was added Hünig's base (1.0 mL, 5.7 mmol) and the resulting mixturewas heated at reflux for 15 h. The mixture was then poured into NaHCO₃(aq) and extracted three times with DCM. The combined organic layerswere dried and concentrated and the crude mixture was purified by columnchromatography to afford the title compound. LCMS [M+H]⁺ 328; ¹H NMR(400 MHz, CD₃OD) δ_(H) ppm 7.80-7.85 (m, 2H), 7.41 (d, J=8.6 Hz, 2H),5.76-5.81 (m, 1H), 3.54-3.64 (m, 2H), 2.95 (t, J=7.1 Hz, 2H).

Intermediate 26 4-chloro-6-(2,3,4-trichlorophenyl)pyrimidin-2-amine

A mixture of 4,6-dichloropyrimidin-2-amine (82 mg, 0.50 mmol),(2,3,4-trichlorophenyl)-boronic acid (113 mg, 0.50 mmol), potassiumcarbonate (138 mg, 1.0 mmol) and palladiumtetrakis(triphenylphosphine)palladium (0) (14 mg, 0.013 mmol) in1,4-dioxane/water (8 mL; 4:1) was heated in a sealed tube at 90° C. for2 h. The reaction mixture was run through a plug of silica (EtOAc) andthen concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 308.

Intermediate 27 6-chloro-4-N-ethylpyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (1 g, 6.09 mmol, 1 eq.)in n-BuOH (18 mL) were added ethaneamine (2M, 3.0 mL, 6.09 mmol, 1 eq.)and Hünig's base (1.17 mL, 6.70 mmol, 1.1 eq.). The reaction mixture wasstirred overnight at 95° C. Ethaneamine (1 eq) was added and thereaction was stirred overnight at 95° C. until complete consumption ofstarting material (2 additions). The solvent was removed in vacuo. Thecrude product was taken up in EtOAc and H₂O. The aqueous layer wasextracted twice with EtOAc and once with CHCl₃/^(i)PrOH (3:1). Thecombined organic layers were washed with brine, dried over MgSO₄ andconcentrated to afford the desired product as a white solid. LCMS [M+H]⁺173; ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.76 (1H, s), 4.79 (3H, br s), 3.26(2H, br s), 1.20 (3H, t, J=7.2 Hz).

Intermediate 28 6-chloro-4-N-cyclohexylpyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (1 g, 6.09 mmol, 1 eq.)in n-BuOH (18 mL) were added cyclohexanamine (698 μL, 6.09 mmol, 1 eq.)and Hünig's base (1.17 mL, 6.70 mmol, 1.1 eq.). The reaction mixture wasstirred overnight at 95° C. Cyclohexanamine (1 eq) was added and thereaction was stirred overnight at 95° C. until complete consumption ofstarting material (2 additions). The solvent was removed in vacuo. Thecrude product was taken up in EtOAc and H₂O. The aqueous layer wasextracted twice with EtOAc and once with CHCl₃/^(i)PrOH (3:1). Thecombined organic layers were washed with brine, dried over MgSO₄ andconcentrated to afford the desired product as a white solid. LCMS [M+H]⁺227; ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.73 (1H, s), 4.97 (2H, s), 4.79 (1H,br s), 3.45 (1H, br s), 1.97-1.92 (2H, m), 1.74-1.69 (2H, m), 1.63-1.58(1H, m), 1.39-1.32 (2H, m), 1.22-1.10 (2H, m).

Intermediate 29 6-chloro-4-N-(cyclopropylmethyl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (250 mg, 1.52 mmol, 1eq.) in n-BuOH (4.5 mL) were added cyclopropylmethanamine (131 μL, 6.09mmol, 1 eq.) and Hünig's base (292 μL, 6.70 mmol, 1.1 eq.). The reactionmixture was stirred overnight at 95° C. The solvent was removed invacuo. The crude product was taken up in EtOAc and H₂O. The aqueouslayer was extracted twice with EtOAc and once with CHCl₃/^(i)PrOH (3:1).The combined organic layers were washed with brine, dried over MgSO₄ andconcentrated to afford the desired product as a white solid. LCMS [M+H]⁺199; ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.75 (1H, s), 4.92 (3H, br s), 3.07(2H, s), 1.04-0.96 (1H, m), 0.55-0.49 (2H, m), 0.23-0.19 (2H, m).

Intermediate 306-chloro-4-N-[(1R)-1-cyclopropylethyl]pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (250 mg, 1.52 mmol, 1eq.) in n-BuOH (4.5 mL) were added (1R)-1-cyclopropylethan-1-amine (141μL, 6.09 mmol, 1 eq.) and Hünig's base (292 μL, 6.70 mmol, 1.1 eq.). Thereaction mixture was stirred overnight at 95° C. The solvent was removedin vacuo. The crude product was taken up in EtOAc and H₂O. The aqueouslayer was extracted twice with EtOAc and once with CHCl₃/^(i)PrOH (3:1).The combined organic layers were washed with brine, dried over MgSO₄ andconcentrated to afford the desired product as a colourless oil (321 mg,99%). LCMS [M+H]⁺ 213; ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.71 (1H, s), 4.97(2H, s), 4.86 (1H, br s), 3.23 (1H, s), 1.19 (3H, d, J=6.4 Hz),0.89-0.81 (1H, m), 0.52-0.41 (2H, m), 0.31-0.25 (1H, m), 0.23-0.18 (1H,m).

Intermediate 31 6-chloro-4-N-(propan-2-yl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (500 mg, 3.05 mmol, 1eq.) in n-BuOH (9 mL) were added propan-2-amine (262 μL, 6.09 mmol, 1eq.) and Hünig's base (584 μL, 6.70 mmol, 1.1 eq.). The reaction mixturewas stirred overnight at 95° C. The solvent was removed in vacuo. Thecrude product was taken up in EtOAc and H₂O. The aqueous layer wasextracted twice with EtOAc and once with CHCl₃/^(i)PrOH (3:1). Thecombined organic layers were washed with brine, dried over MgSO₄ andconcentrated to afford the desired product as a white solid (569 mg,99%). LCMS [M+H]⁺ 187; ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.74 (1H, s), 4.76(2H, s), 4.60 (1H, br s), 3.85 (1H, br s), 1.19 (3H, s), 1.18 (3H, s).

Intermediate 326-chloro-4-N-[(1S)-1-cyclopropylethyl]pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (250 mg, 1.52 mmol, 1eq.) in n-BuOH (4.5 mL) were added (1S)-1-cyclopropylethan-1-amine (141μL, 6.09 mmol, 1 eq.) and Hünig's base (292 μL, 6.70 mmol, 1.1 eq.). Thereaction mixture was stirred overnight at 95° C. The solvent was removedin vacuo. The crude product was taken up in EtOAc and H₂O. The aqueouslayer was extracted twice with EtOAc and once with CHCl₃/^(i)PrOH (3:1).The combined organic layers were washed with brine, dried over MgSO₄ andconcentrated to afford the desired product as a colourless oil (296 mg,91%). LCMS [M+H]⁺ 213; ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.71 (1H, s), 4.99(2H, s), 4.89 (1H, br s), 3.23 (1H, s), 1.19 (3H, d, J=6.4 Hz),0.88-0.81 (1H, m), 0.50-0.40 (2H, m), 0.31-0.25 (1H, m), 0.23-0.17 (1H,m).

Intermediate 336-chloro-4-N-[2-(4-methanesulfonylphenyl)ethyl]pyrimidine-2,4-diamine

A mixture of 4,6-dichloropyrimidin-2-amine (500 mg, 3.0 mmol),2-(4-methylsulfonylphenyl)ethanamine (600 mg, 3.0 mmol) and Hünig's base(0.63 mL, 3.6 mmol) in 2-propanol (10 mL) was heated at reflux for 15 h.The reaction mixture was poured into NaHCO₃ (aq) and extracted threetimes with DCM. The combined organic layers were dried and concentrated.The crude mixture was purified by column chromatography which affordedthe title compound. LCMS [M+H]+ 327; ¹H NMR (400 MHz, CDCl3) δ ppm 7.90(d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 5.77 (s, 1H), 4.80-4.89 (m,2H), 4.69-4.79 (m, 1H), 3.56-3.67 (m, 2H), 3.07 (s, 3H), 3.00 (t, J=6.8Hz, 2H).

Intermediate 34 6-chloro-4-N-(2,2-dimethylpropyl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (250 mg, 1.52 mmol, 1eq.) in n-BuOH (9 mL) were added 2,2-dimethylpropan-1-amine (6.09 mmol,1 eq.) and Hünig's base (292 μL, 6.70 mmol, 1.1 eq.). The reactionmixture was stirred overnight at 95° C. The solvent was removed invacuo. The crude product was taken up in EtOAc and H₂O. The aqueouslayer was extracted twice with EtOAc and once with CHCl₃/^(i)PrOH (3:1).The combined organic layers were washed with brine, dried over MgSO₄ andconcentrated to afford the desired product as a white solid. LCMS [M+H]⁺215; ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.94 (1H, s), 3.24 (2H, br s), 0.98(9H, s).

Intermediate 354-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Step 1: To a suspension of 4,6-dichloropyrimidin-2-amine (500 mg, 3.05mmol) and Hünig's base (0.80 mL) in 2-propanol (3.0 mL) was addedtert-butyl N-(2-aminoethyl)carbamate (586 mg, 3.66 mmol) and the mixturewas stirred at 150° C. for 15 min. The crude mixture was poured intoNaHCO3 (aq) and extracted three times with DCM. The combined organiclayers were dried and concentrated. Purification by columnchromatography (0→10% MeOH in DCM) afforded tert-butylN-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]carbamate (850 mg,2.95 mmol).

Step 2: tert-ButylN-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]carbamate (850 mg,2.95 mmol), (2,3-dimethylphenyl)boronic acid (532 mg, 3.55 mmol),palladium tetrakis(triphenylphosphine)palladium (0) (34 mg, 0.030 mmol),and K₂CO₃ (1020 mg, 7.39 mmol) were suspended in 1,4-dioxane (10 ml) andH₂O (2.0 ml). The vial was flushed with nitrogen and the resultingmixture was stirred at 90° C. for 16 h. The crude mixture was pouredinto NaHCO3 (aq) and extracted three times with DCM. The combinedorganic layers were dried and concentrated. Purification by columnchromatography (0→10% MeOH in DCM) afforded tert-butylN-[2-[[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino]ethyl]carbamate(770 mg, 2.15 mmol).

Step 3: tert-ButylN-[2-[[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino]ethyl]carbamate(770 mg, 2.15 mmol) was dissolved in TFA (6 mL) and the resultingmixture was stirred for 1 h at rt, after which the TFA was distilledoff. Purification by column chromatography (5>30% MeOH [containing 1 v/v% NH₄OH] in DCM) afforded4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (500 mg,1.94 mmol). LCMS [M+H]⁺ 258.

Intermediate 364-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Step 1: A vial was charged with 4,6-dichloropyrimidin-2-amine (500 mg,3.0 mmol) and tert-butyl N-(2-aminopropyl)carbamate (640 mg, 3.7 mmol).Then 2-propanol (3.0 ml) and Hünig's base (0.80 ml) were added and theresulting mixture was heated at 150° C. using microwave irradiation for15 min. The mixture was then concentrated and purified by columnchromatography (2→10% MeOH in DCM) to afford tert-butylN-[3-[(2-amino-6-chloro-pyrimidin-4-yl)amino]propyl]-carbamate (788 mg,2.61 mmol).

Step 2: tert-ButylN-[3-[(2-amino-6-chloro-pyrimidin-4-yl)amino]propyl]carbamate (790 mg,2.6 mmol), (2,3-dimethylphenyl)boronic acid (470 mg, 3.1 mmol),palladium tetrakis(triphenylphosphine)palladium (0) (60 mg, 0.050 mmol),and K₂CO₃ (720 mg 5.2 mmol) were suspended in 1,4-dioxane (6.0 ml) andH₂O (1.5 ml). The resulting mixture was heated at 90° C. for 16 h andthen poured into H₂O and extracted three times with DCM. The combinedorganic layers were dried and concentrated. Purification by columnchromatography (1→10% MeOH in DCM) afforded tert-butylN-[3-[[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino]propyl]carbamate(800 mg, 2.1 mmol).

Step 3: tert-ButylN-[3-[[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino]propyl]carbamate(800 mg, 2.1 mmol) was dissolved in TFA and heated at reflux for 1 h.The TFA was evaporated and the crude residue was purified by columnchromatography (2→30% MeOH [containing 1 v/v % NH₄OH] in DCM) to afford4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (540mg, 2.0 mmol). LCMS [M+H]⁺ 272.

Intermediate 37 4-chloro-6-(2-chloro-3-methyl phenyl)pyrimidin-2-amine

To a suspension of 4,6-dichloropyrimidin-2-amine (250 mg, 1.52 mmol, 1eq) in dioxane/H₂O (5 mL, 4:1) was added(2-chloro-3-methylphenyl)boronic acid (260 mg, 1.52 mmol, 1 eq) followedby potassium carbonate (421 mg, 3.05 mmol, 2 eq) and Pd(PPh₃)₄ (44 mg,0.04 mmol, 0.025 eq). The resulting mixture was stirred at 90° C. for 12hrs. The solvent was removed in vacuo. The residue was taken up in DMFand purified by preparative to afford the desired product as anoff-white solid (166 mg, 43%). LCMS [M+H]⁺ 254; ¹H NMR (400 MHz, CDCl₃)δ_(H) 7.32-7.28 (2H, m), 7.25-7.21 (1H, m), 6.92 (1H, s), 5.31 (2H, brs), 2.42 (3H, 5).

Intermediate 38 4-chloro-6-(quinolin-5-yl)pyrimidin-2-amine

To a suspension of 4,6-dichloropyrimidin-2-amine (150 mg, 0.91 mmol, 1eq) in dioxane/H₂O (5 mL, 4:1) was added (quinolin-5-yl)boronic acid(158 mg, 0.91 mmol, 1 eq) followed by potassium carbonate (253 mg, 1.83mmol, 2 eq) and Pd(PPh₃)₄ (26 mg, 0.020 mmol, 0.025 eq). The resultingmixture was stirred at 90° C. for 12 hrs. The solvent was removed invacuo and the residue was purified by preparative HPLC to afford thedesired product as a yellow solid (63 mg, 27%). LCMS [M+H]⁺ 257; ¹H NMR(400 MHz, CDCl₃) δ_(H) 9.21-9.19 (2H, m), 8.62 (1H, d, J=8.8 Hz),8.30-7.99 (1H, m), 7.92 (1H, dd, J=7.2 and 0.8 Hz), 7.81-7.77 (1H, m),6.98 (1H, s), 5.40 (2H, br s).

Intermediate 39 4-chloro-6-(1H-indol-4-yl)pyrimidin-2-amine

To a suspension of 4,6-dichloropyrimidin-2-amine (150 mg, 0.91 mmol, 1eq) in dioxane/H₂O (5 mL, 4:1) was added (1H-indol-4-yl)boronic acid(147 mg, 0.91 mmol, 1 eq) followed by potassium carbonate (253 mg, 1.83mmol, 2 eq) and Pd(PPh₃)₄ (26 mg, 0.02 mmol, 0.025 eq). The resultingmixture was stirred at 90° C. for 12 hrs. The solvent was removed invacuo and the residue was purified by preparative HPLC to afford thedesired product as a yellow solid (111 mg, 50%). LCMS [M+H]⁺ 245; ¹H NMR(400 MHz, CDCl₃) δ_(H) 8.45 (1H, br s), 7.57 (1H, d, J=7.2 Hz), 7.51(1H, d, J=8.0 Hz), 7.35 (1H, t, J=4.0 Hz), 7.27 (1H, d, J=7.6 Hz), 7.18(1H, s), 7.00-6.99 (1H, m), 5.90 (2H, br s).

Intermediate 40 4-chloro-6-(5-chloro-2-methyl phenyl)pyrimidin-2-amine

To a suspension of 4,6-dichloropyrimidin-2-amine (150 mg, 0.91 mmol, 1eq) in dioxane/H₂O (5 mL, 4:1) was added(5-chloro-2-methylphenyl)boronic acid (155 mg, 0.91 mmol, 1 eq) followedby potassium carbonate (253 mg, 1.83 mmol, 2 eq) and Pd(PPh₃)₄ (26 mg,0.02 mmol, 0.025 eq). The resulting mixture was stirred at 90° C. for 12hrs. The solvent was removed in vacuo and the residue was purified bypreparative HPLC to afford the desired product as an off-white solid (98mg, 42%). LCMS [M+H]⁺ 254; ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.35 (1H, d,J=2.0 Hz), 7.28 (1H, dd, J=8.4 and 2.4 Hz), 7.18 (1H, d, J=8.4 Hz), 6.72(1H, s), 5.30 (2H, br s), 2.34 (3H, s).

Intermediate 41 6-(3-aminophenyl)-4-N-methylpyrimidine-2,4-diamine

Tetrakis(triphenylphosphine)palladium (0) (5 mol %) was added to astirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (1.00mmol), (3-aminophenyl)boronic acid (1.3 eq.), sodium carbonate (3.2eq.), 1,4-dioxane (4 mL) and water (1 mL) in a tube. The tube was sealedand the reaction was heated at 90° C. for 5 h and then concentrated. Thecrude material was taken up in ethyl acetate and washed with water. Theorganic phase was dried over magnesium sulfate, concentrated andpurified by flash chromatography (0→15% MeOH in DCM) to give the titlecompound. LCMS [M+H]⁺ 216.

Intermediate 426-(3-amino-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Tetrakis(triphenylphosphine)palladium (0) (5 mol %) was added to astirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (3.00mmol), (3-amino-2-methylphenyl)boronic acid (1.3 eq.), sodium carbonate(3.2 eq.), 1,4-dioxane (4 mL) and water (1 mL). The tube was sealed andthe reaction was heated at 90° C. for 5 h. The mixture was concentratedand purified by column chromatography (13% MeOH in DCM) to give thetitle compound. LCMS [M+H]⁺ 230; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.88(1H, t, J=7.71 Hz), 6.71-6.81 (1H, m), 6.61 (1H, dd, J=7.96, 1.14 Hz),6.44 (1H, dd, J=7.58, 1.01 Hz), 5.90 (2H, br. s.), 5.64 (1H, s), 4.83(2H, s), 2.75 (3H, d, J=4.55 Hz), 1.98 (3H, s).

Intermediate 436-(5-amino-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Tetrakis(triphenylphosphine)palladium (0) (5 mol %) was added to astirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (3.0 mmol),(5-amino-2-methylphenyl)boronic acid (1.3 eq.), sodium carbonate (3.2eq.), 1,4-dioxane (4 mL) and water (1 mL) in a tube. The tube was sealedand the reaction was heated at 90° C. for 5 h. The mixture wasconcentrated and purified by column chromatography (13% MeOH in DCM) togive the title compound. LCMS [M+H]⁺ 230.

Intermediate 44 6-(4-aminophenyl)-4-N-methylpyrimidine-2,4-diamine

Tetrakis(triphenylphosphine)palladium (0) (5 mol %) was added to astirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (1.0 mmol),4-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.3 eq.), sodiumcarbonate (3.2 eq.), 1,4-dioxane (4 mL) and water (1 mL) in a tube. Thetube was sealed and the reaction was heated at 90° C. for 5 h and thenconcentrated. The crude material was taken up in ethyl acetate andwashed with water. The organic phase was dried over magnesium sulfate,concentrated and purified by flash chromatography (0→15% MeOH/DCM) togive the title compound. LCMS [M+H]⁺ 216; ¹H NMR (400 MHz, CDCl₃) δ_(H)ppm 7.64 (2H, d, J=8.53 Hz), 6.50-6.62 (3H, m), 6.03 (1H, s), 5.74 (2H,s), 5.37 (2H, s), 2.76 (3H, d, J=4.77 Hz).

General procedures

General Procedure 1:

To a mixture of 4-chloro-6-phenylpyrimidin-2-amine (1 equiv.) is addedHünig's base (3.4 equiv.) and an appropriate amine (1.6 equiv.) in DMF(500 μL). The mixture is heated at 120° C. overnight. The crude mixtureis purified by preparative HPLC to afford the desired product.

General Procedure 2:

To a mixture of a suitable chloropyrimidine derivative (1 equiv.) in1,4-dioxane/water (4:1) is added the appropriate boronic acid (orboronic ester) derivative (1.3 equiv.), K₂CO₃ (2 equiv.) and Pd(PPh₃)₄(0.1 equiv.). The mixture is heated at 95° C. overnight or in amicrowave reactor until the reaction is complete as shown by LCMS. Thecrude mixture is purified by preparative HPLC to afford the desiredproduct.

General Procedure 3:

To a mixture of a suitable chloropyrimidine derivative (1 equiv.) isadded Hünig's base (3.4 equiv.) and an appropriate amine (1.6 equiv.) inn-BuOH (500 μL). The mixture is heated at 95° C. overnight. The crudemixture was purified by preparative HPLC to afford the desired product.

General Procedure 4:

A solution of an appropriate chloropyrimidine derivative (1 equiv.) inammonium hydroxide (25% aq.) is heated in the microwave at 120° C. untilcompletion of the reaction as monitored by LCMS. The solvent is thenevaporated and the product is dried under vacuum. Further purificationby preparative HPLC is performed when required.

General Procedure 5:

To a mixture of a suitable chloropyrimidine derivative (1 equiv.) inDMF/water (9:1) is added the appropriate boronic acid (or boronic ester)derivative (1.1 equiv.), Na₂CO₃ (2 equiv.) and Pd(PPh₃)₄ (0.1 equiv.).The mixture is heated at 120° C. overnight or in the microwave until thereaction is complete as shown by LCMS. The crude mixture is thenpurified by preparative HPLC to afford the desired product.

General Procedure 6:

To a mixture of a suitable iodopyrimidine derivative (1 equiv.) inDMF/water (20:1) is added the appropriate boronic acid (or boronicester) derivative (1.3 equiv.), Na₂CO₃ (2 equiv.) and Pd(PPh₃)₄ (0.1equiv.). The mixture is heated at 120° C. overnight or in a microwavereactor until the reaction is complete as shown by LCMS. The crudemixture is then purified by HPLC to afford the desired product.

General Procedure 7:

A mixture of a suitable 6-aryl-4-chloropyrimidin-2-amine (1 equiv.), asuitable amine (1.5 equiv.) and triethylamine (2 equiv.) in n-butanol(1.5 mL) is heated in a sealed tube at 95° C. overnight. Concentratedand purified by preparative HPLC to give the desired product.

General Procedure 8: To a mixture of a suitable4-chloropyrimidin-2-amine (1 equiv.) in 1,4-dioxane/water (4:1) is addedthe desired boronic acid (or boronic ester) (1.3 equiv.), K₂CO₃ (2equiv.) and Pd(PPh₃)₄ (0.1 equiv.). The mixture is heated at 95° C.overnight or in a microwave until the reaction is complete as shown byLCMS. The crude mixture is purified by HPLC to afford the desiredproduct.

General Procedure 9:

A mixture of a suitable amine (1 equiv.), and a suitablechloropyrimidine derivative (1.2 equiv.) and triethylamine (1.5 equiv.)in 2-propanol (1.0 mL) is heated in a sealed tube at 95° C. overnight orat 150° C. for 15 min in a microwave reactor. The reaction mixture isthen concentrated and purified by preparative HPLC or by silica gelchromatography.

General Procedure 10:

A mixture of an4-N-(aminoalkyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (1.0equiv.), a suitable sulfonyl chloride (1.2 equiv.), and triethylamine(1.5 equiv.) in DCM or MeCN (1.0 mL) is stirred in a sealed tube at rtor 50° C. After completion the crude mixture is concentrated andpurified by preparative HPLC or by silica gel chromatography.

General Procedure 11:

A mixture of4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (1.0eq.) and the corresponding isocyanate (1.05 eq.) is dissolved in DCM.The resulting reaction mixture is stirred at rt until completionaccording to LCMS. The mixture is then concentrated and purified bypreparative HPLC or by silica gel chromatography.

General Procedure 12:

A mixture of4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (1.0equiv.) and the corresponding heteroaryl chloride (1.5 equiv.), andHünig's base (1.5 equiv.) in 2-propanol (0.5 mL) is stirred in a sealedtube at 150° C. in a microwave reactor for 30 min. The crude mixture isthen concentrated and purified by preparative HPLC or by silica gelchromatography.

EXAMPLES

The utility of the compounds of the present invention can beillustrated, for example, by their activity in vitro in the cancer cellclonogenic and/or viability assay described below. The link betweenactivity in tumor cell clonogenic assay and anti-tumor activity in theclinical setting has been well established in the art (e.g. see refSilverstini et al Stem Cells 1993, 11(6), 258-35).

Example 1 4-N-cyclohexyl-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from cyclohexanamine and4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 269; ¹H NMR (400 MHz,DMSO-d₆) δ_(H) 8.79-8.61 (1H, m), 7.78-7.67 (2H, m), 7.66-7.55 (3H, m),6.33 (1H, s), 4.05-3.85 (1H, m), 2.00-1.83 (2H, m), 1.80-1.70 (2H, m),1.41-1.10 (6H, m).

Example 2 4-N-ethyl-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from ethanamine and4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 215; ¹H NMR (400 MHz,DMSO-d₆) δ_(H) 8.82 (1H, s), 7.74-7.71 (2H, m), 7.67-7.57 (3H, m), 6.33(1H, s), 3.53-3.41 (2H, m), 1.18 (3H, t, J=7.1 Hz).

Example 3 4-N-(3-ethoxypropyl)-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from 3-ethoxypropan-1-amineand 4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 273; ¹H NMR (400MHz, DMSO-d₆) δ_(H) 8.82 (1H, s), 7.74-7.71 (2H, m), 7.63-7.59 (3H, m),6.37 (1H, s), 3.45-3.41 (6H, m), 1.80 (2H, q, J=6.5 Hz), 1.11 (3H, t,J=6.5 Hz).

Example 4 6-phenyl-4-N-propylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from phenylboronic acid and6-chloro-4-N-propylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 229.

Example 5 6-(4-methanesulfonylphenyl)-4-N-propylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from(4-methane-sulfonylphenyl)boronic acid and6-chloro-4-N-propylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 307; ¹H NMR (400MHz, DMSO-d₆) δ_(H) 8.21-8.11 (2H, m), 8.05-7.92 (2H, m), 6.42 (1H, s),3.50-3.40 (2H, m), 3.31 (3H, s), 1.68-1.51 (2H, m), 0.94 (3H, t, J=7.1Hz).

Example 6 4-N-(cyclopropylmethyl)-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from cyclopropylmethanamineand 4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 241; ¹H NMR (400MHz, DMSO-d₆) δ_(H) 8.92 (1H, s), 7.83-7.50 (5H, m), 6.39 (1H, s),3.33-3.20 (2H, m), 1.15-0.95 (1H, m), 0.51 (1H, d, J=5.8 Hz), 0.27 (1H,d, J=5.8 Hz).

Example 7 4-N-(oxan-4-yl)-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from oxan-4-amine and4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 271.

Example 8 4-N-(furan-2-ylmethyl)-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from furan-2-ylmethanamine and4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 267.

Example 9 4-N-(pentan-3-yl)-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from pentan-3-amine and4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 257.

Example 10 6-phenyl-4-N-(propan-2-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 1 from propan-2-amine and4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 229.

Example 11 4-N-benzyl-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from phenylmethanamine and4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 277; ¹H NMR (400 MHz,DMSO-d₆) δ_(H) 7.92-7.84 (2H, m), 7.48-7.40 (4H, m), 7.37-7.27 (4H, m),7.27-7.20 (1H, m), 6.29 (1H, s), 6.06 (2H, s), 4.54 (2H, d, J=5.9 Hz).

Example 12 4-N-[2-(morpholin-4-yl)ethyl]-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from2-(morpholin-4-yl)ethan-1-amine and 4-chloro-6-phenylpyrimidin-2-amine.LCMS [M+H]⁺ 300.

Example 13 6-(4-chlorophenyl)-4-N-cyclopropylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from cyclopropanamine and4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 261.

Example 14 4-N-tert-butyl-6-(4-chlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-chlorophenyl)boronicacid and 4-N-tert-butyl-6-chloropyrimidine-2,4-diamine. LCMS [M+H]⁺ 277;¹H NMR (400 MHz, DMSO-d₆) δ_(H) 8.38 (1H, s), 7.75-7.66 (4H, m), 6.38(1H, s), 1.46 (9H, s).

Example 15 6-(4-chlorophenyl)-4-N-(oxan-4-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-chlorophenyl)boronicacid and 6-chloro-4-N-(oxan-4-yl)pyrimidine-2,4-diamine. LCMS [M+H]⁺305.

Example 164-N-cyclopropyl-6-[3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from[3-(trifluoromethyl)phenyl]-boronic acid and6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 295.

Example 17 4-N-tert-butyl-6-(4-methoxyphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-methoxyphenyl)boronicacid and 4-N-tert-butyl-6-chloropyrimidine-2,4-diamine. LCMS [M+H]⁺ 273;¹H NMR (400 MHz, DMSO-d₆) δ_(H) 7.65 (2H, d, J=9.4 Hz), 7.15 (2H, d,J=9.4 Hz), 6.35 (1H, s), 3.85 (3H, s), 1.45 (9H, s).

Example 18 4-N-cyclopropyl-6-(4-methoxyphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-methoxyphenyl)boronicacid and 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺257; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 7.79-7.72 (2H, m), 7.17-7.15 (2H,m), 6.24 (1H, s), 3.85 (4H, s), 0.83-0.81 (2H, m), 0.62-0.60 (2H, m).

Example 19 6-(3-chlorophenyl)-4-N-cyclopropylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (3-chlorophenyl)boronicacid and 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺261; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.78-7.76 (1H, m), 7.64-7.57 (3H, m),6.27 (1H, s), 0.89-0.87 (2H, m), 0.70-0.63 (3H, m).

Example 204-N-tert-butyl-6-[3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from[3-(trifluoromethyl)phenyl]boronic acid and4-N-tert-butyl-6-chloropyrimidine-2,4-diamine. LCMS [M+H]⁺ 311.

Example 21 6-(3-chlorophenyl)-4-N-(oxan-4-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (3-chlorophenyl)boronicacid and 6-chloro-4-N-(oxan-4-yl)pyrimidine-2,4-diamine. LCMS [M+H]⁺305; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.78-7.76 (1H, m), 7.65-7.63 (2H, m),7.59-7.57 (1H, m), 6.30 (1H, s), 4.30-4.28 (1H, m), 4.02-3.98 (2H, m),3.53-3.51 (2H, m), 2.01-2.00 (2H, m), 1.65-1.63 (2H, m).

Example 22 4-N-tert-butyl-6-(3-chlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (3-chlorophenyl)boronicacid and 4-N-tert-butyl-6-chloropyrimidine-2,4-diamine. LCMS [M+H]⁺ 277;¹H NMR (400 MHz, CD₃OD) δ_(H) 7.75-7.73 (1H, m), 7.65-7.62 (2H, m),7.59-7.55 (2H, m), 1.52 (9H, s).

Example 234-N-methyl-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 394; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.36 (1H, s), 8.07 (1H, d, J=8.3 Hz), 7.93 (2H, d,J=8.3 Hz), 7.83 (1H, d, J=7.9 Hz), 7.51-7.44 (1H, m), 7.43-7.31 (3H, m),6.46 (1H, s), 3.04 (3H, s), 2.37 (3H, s).

Example 246-(2,3-dichlorophenyl)-4-N-(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from(2,3-dichlorophenyl)boronic acid and6-chloro-4-N-(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺337.

Example 256-(3-chlorophenyl)-4-N-(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (3-chlorophenyl)boronicacid and 6-chloro-4-N-(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 303.

Example 266-[1-(benzenesulfonyl)-1H-indol-3-yl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(benzenesulfonyl)-1H-indol-3-yl]boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 380; ¹H NMR (400MHz, DMSO-d₆) δ_(H) 8.43-8.25 (2H, m), 8.10-8.03 (2H, m), 8.01-7.95 (1H,m), 7.77-7.68 (1H, m), 7.66-7.56 (2H, m), 7.46-7.26 (2H, m), 6.74 (1H,br s), 6.32 (1H, s), 6.02 (2H, s), 2.81 (3H, d, J=5.0 Hz).

Example 274-N-cyclopropyl-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine.

LCMS [M+H]⁺ 420; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.14 (1H, s), 8.07 (1H,d, J=7.9 Hz), 8.01 (1H, d, J=8.2 Hz), 7.86 (2H, d, J=8.2 Hz), 7.43-7.23(4H, m), 6.43 (1H, s), 2.65 (1H, s), 2.34 (3H, s), 0.88-0.74 (2H, m),0.65-0.48 (2H, m).

Example 286-[1-(benzenesulfonyl)-1H-indol-3-yl]-4-N-cyclopropylpyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(benzenesulfonyl)-1H-indol-3-yl]boronic acid and6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 406; ¹H NMR(400 MHz, CD₃OD) δ_(H) 8.16 (1H, s), 8.10-7.98 (4H, m), 7.66-7.58 (1H,m), 7.56-7.46 (2H, m), 7.43-7.25 (2H, m), 6.43 (1H, s), 2.66 (1H, s),0.84-0.81 (2H, m), 0.58-0.55 (2H, m).

Example 296-[1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 381; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.55 (1H, d, J=8.2 Hz), 8.41-8.30 (2H, m), 8.22-8.11(2H, m), 7.71-7.61 (1H, m), 7.57-7.50 (2H, m), 7.37-7.28 (1H, m), 6.27(1H, s), 2.92 (3H, s).

Example 306-[1-(benzenesulfonyl)-1H-indol-4-yl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(benzenesulfonyl)-1H-indol-4-yl]boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 380; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.08 (1H, d, J=8.2 Hz), 7.97-7.89 (2H, m), 7.73 (1H,d, J=3.8 Hz), 7.65-7.56 (1H, m), 7.53-7.45 (3H, m), 7.39 (1H, t, J=8.2Hz), 7.10 (1H, d, J=3.8 Hz), 6.10 (1H, s), 2.89 (3H, s).

Example 316-[1-(benzenesulfonyl)-1H-indol-5-yl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(benzenesulfonyl)-1H-indol-5-yl]boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 380; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.07-7.99 (2H, m), 7.98-7.89 (2H, m), 7.83-7.74 (1H,m), 7.71 (1H, d, J=4.0 Hz), 7.64-7.55 (1H, m), 7.54-7.45 (2H, m), 6.80(1H, d, J=4.0 Hz), 6.21 (1H, s), 2.90 (3H, s).

Example 32 6-(2-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2-methoxyphenyl)boronicacid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 231; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.50 (1H, dd, J=7.5 and 1.7 Hz), 7.41-7.36(1H, m), 7.08 (1H, d, J=8.3 Hz), 7.01 (1H, td, J=7.5 and 1.0 Hz), 6.17(1H, s), 3.84 (3H, s), 2.89 (3H, s).

Example 33 6-(4-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-methoxyphenyl)boronicacid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 231.

Example 346-[3,5-bis(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from[3,5-bis(trifluoromethyl)phenyl]boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 337; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.31 (2H, s), 8.17 (1H, s), 7.55-7.20 (3H, br s), 6.45(1H, s), 3.02 (3H, s).

Example 35 6-(isoquinolin-4-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (isoquinolin-4-yl)boronicacid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 252; ¹HNMR (400 MHz, CD₃OD) δ_(H) 9.17 (1H, s), 8.78 (1H, s), 8.17 (1H, d,J=8.4 Hz), 8.12 (1H, d, J=8.1 Hz), 7.98-7.94 (1H, m), 7.80-7.77 (1H, m),6.54 (1H, s), 3.10 (3H, s).

Example 364-N-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from[4-(trifluoromethyl)phenyl]boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 269; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.93-7.87 (4H, m), 6.38 (1H, s), 3.04 (3H, s).

Example 374-N-methyl-6-[3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from[3-(trifluoromethyl)phenyl]boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 269; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.05 (1H, s), 7.99 (1H, d, J=8.0 Hz), 7.92 (1H, d,J=8.0 Hz), 7.79 (1H, t, J=8.0 Hz), 6.38 (1H, s), 3.05 (3H, s).

Example 38 6-(2,3-dichlorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 3 from methanamine and4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 269; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.79-7.77 (1H, m), 7.50-7.49 (2H, m), 6.12(1H, s), 3.04 (3H, s).

Example 39 6-(2H-1,3-benzodioxol-5-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from(2H-1,3-benzodioxol-5-yl)boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 245; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.42-7.39 (1H, m), 7.36-7.35 (1H, m), 6.89 (1H, d,J=8.0 Hz), 6.15 (1H, s), 6.02 (1H, s), 2.92 (3H, s).

Example 40 3-[2-amino-6-(methylamino)pyrimidin-4-yl]benzonitrile

Prepared according to general procedure 2 from (3-cyanophenyl)boronicacid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 226; ¹HNMR (400 MHz, CD₃OD) δ_(H) 8.15 (1H, s), 8.05-8.03 (1H, m), 7.95-7.92(1H, m), 7.74 (1H, t, J=8.5 Hz), 6.35 (1H, s), 3.02 (3H, s).

Example 41 N-{3-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}acetamide

Prepared according to general procedure 2 from(3-acetamidophenyl)boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 258; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.20 (1H, s), 7.56-7.52 (2H, m), 7.45-7.43 (1H, m),6.31 (1H, s), 3.06 (3H, s), 2.19 (3H, s).

Example 424-N-methyl-6-[4-(morpholine-4-sulfonyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from[4-(morpholine-4-sulfonyl)phenyl]boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 350; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.99 (4H, s), 6.42 (1H, s), 3.76-3.72 (4H, m), 3.07(3H, s), 3.06-3.03 (4H, m).

Example 43 6-(4-methanesulfonylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from(4-methanesulfonyl-phenyl)boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 279; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.20-8.17 (2H, m), 8.00-7.97 (2H, m), 6.41 (1H, s),3.22 (3H, s), 3.08 (3H, s).

Example 444-N-methyl-6-[3-(morpholine-4-carbonyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from[3-(morpholine-4-carbonyl)phenyl]boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 314; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.00-7.96 (1H, m), 7.92 (1H, s), 7.57 (1H, t, J=7.8Hz), 7.52 (1H, dt, J=7.8 and 1.4 Hz), 6.27 (1H, s), 3.79-3.50 (8H, m),2.94 (3H, s).

Example 454-[2-amino-6-(methylamino)pyrimidin-4-yl]-N-(furan-2-ylmethyl)benzamide

Prepared according to general procedure 2 from{4-[(furan-2-ylmethyl)carbamoyl]phenyl}boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 324; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.93-7.90 (4H, m), 7.46-7.44 (1H, m), 6.39-6.37 (1H,m), 6.34-6.32 (1H, m), 6.28 (1H, s), 4.60 (2H, s), 2.94 (3H, s).

Example 46N-{4-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}methanesulfonamide

Prepared according to general procedure 2 from(4-methanesulfon-amidophenyl)boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 294; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.72-7.70 (2H, m), 7.43-7.40 (2H, m), 6.29 (1H, s),3.06 (3H, s), 3.03 (3H, s).

Example 47 N-{4-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}acetamide

Prepared according to general procedure 2 from(4-acetamidophenyl)boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 258; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.82-7.80 (2H, m), 7.75-7.73 (2H, m), 6.31 (1H, s),3.03 (3H, s), 2.18 (3H, d, J=2.5 Hz).

Example 48 4-N-methyl-6-(pyridin-4-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (pyridin-4-yl)boronicacid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 202; ¹HNMR (400 MHz, CD₃OD) δ_(H) 8.79 (2H, dd, J=4.7 and 1.6 Hz), 7.76 (2H, d,J=4.7 Hz), 6.47 (1H, s), 3.07 (3H, s).

Example 49 6-(6-methoxypyridin-3-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from(6-methoxypyridin-3-yl)boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 232; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.57 (1H, s), 8.03 (1H, d, J=7.3 Hz), 6.98 (1H, d,J=7.3 Hz), 6.30 (1H, s), 4.02 (3H, s), 3.07 (3H, s).

Example 50 6-(2-fluoro-4-phenylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from(2-fluoro-4-phenylphenyl)boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 295; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.75-7.61 (5H, m), 7.54-7.44 (3H, m), 6.41 (1H, s),6.30 (1H, s), 3.06 (3H, s).

Example 51 4-[2-amino-6-(methylamino)pyrimidin-4-yl]benzonitrile

Prepared according to general procedure 2 from (4-cyanophenyl)boronicacid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 226; ¹HNMR (400 MHz, CD₃OD) δ_(H) 8.03 (2H, d, J=8.2 Hz), 7.84-7.80 (2H, m),6.29 (1H, s), 2.93 (3H, s).

Example 52 4-N-methyl-6-(quinolin-5-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (quinolin-5-yl)boronicacid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 252; ¹HNMR (400 MHz, CD₃OD) δ_(H) 8.98 (1H, dd, J=4.2 and 1.9 Hz), 8.49 (1H, d,J=8.6 Hz), 8.26 (1H, d, J=8.6 Hz), 7.95-7.91 (1H, m), 7.82 (1H, d, J=7.2Hz), 7.67 (1H, dd, J=8.6 and 4.2 Hz), 6.23 (1H, s), 3.08 (3H, s).

Example 53 6-(4-chlorophenyl)-4-N-(prop-2-en-1-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-chlorophenyl)boronicacid and 6-chloro-4-N-(prop-2-en-1-yl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 261; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.75-7.73 (2H, m), 7.64-7.62(2H, m), 6.36 (1H, s), 6.02-5.92 (1H, m), 5.33-5.31 (1H, m), 5.23-5.20(1H, m), 4.18-4.16 (2H, m).

Example 546-(4-methoxyphenyl)-4-N-(prop-2-en-1-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-methoxyphenyl)boronicacid and 6-chloro-4-N-(prop-2-en-1-yl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 257.

Example 55 6-(4-chlorophenyl)-4-N-cyclopentylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-chlorophenyl)boronicacid and 6-chloro-4-N-cyclopentylpyrimidine-2,4-diamine. LCMS [M+H]⁺289; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.60 (2H, d, J=8.8 Hz), 7.51-7.49(2H, m), 6.17 (1H, s), 4.36 (1H, s), 2.00-1.93 (2H, m), 1.73-1.65 (2H,m), 1.61-1.53 (2H, m), 1.50-1.43 (2H, m).

Example 56 4-N-cyclopentyl-6-(4-methoxyphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from6-chloro-4-N-cyclopentylpyrimidine-2,4-diamine and(4-methoxyphenyl)boronic acid. LCMS [M+H]⁺ 285; ¹H NMR (400 MHz, CD₃OD)δ_(H) 7.68 (2H, d, J=9.2 Hz), 7.12 (2H, d, J=9.2 Hz), 6.27 (1H, s), 4.47(1H, q, J=6.7 Hz), 3.89 (3H, s), 2.10-2.03 (2H, m), 1.82-1.79 (2H, m),1.72-1.63 (2H, m), 1.62-1.53 (2H, m).

Example 574-N-cyclopentyl-6-[3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from[3-(trifluoromethyl)-phenyl]boronic acid and6-chloro-4-N-cyclopentylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 323; ¹H NMR(400 MHz, CD₃OD) δ_(H) 8.17 (1H, s), 8.08 (1H, d, J=7.9 Hz), 7.74 (1H,d, J=7.9 Hz), 7.65 (1H, t, J=7.9 Hz), 6.28 (1H, s), 4.29 (1H, s),2.09-1.99 (2H, m), 1.75-1.74 (2H, m), 1.71-1.62 (2H, m), 1.60-1.49 (2H,m).

Example 58 6-(4-chlorophenyl)-4-N-cyclobutylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-chlorophenyl)boronicacid and 6-chloro-4-N-cyclobutylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 275;¹H NMR (400 MHz, CD₃OD) δ_(H) 7.83 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4Hz), 6.17 (1H, s), 4.42 (1H, s), 2.44-2.38 (2H, m), 2.02-1.94 (2H, m),1.83-1.76 (2H, m).

Example 59 4-N-cyclobutyl-6-(4-methoxyphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-methoxyphenyl)boronicacid and 6-chloro-4-N-cyclobutylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 271;¹H NMR (400 MHz, CD₃OD) δ_(H) 7.68 (2H, d, J=8.5 Hz), 7.14 (2H, d, J=8.5Hz), 6.22 (1H, s), 4.64 (1H, q, J=7.9 Hz), 3.90 (3H, s), 2.46-2.38 (2H,m), 2.12-2.01 (2H, m), 1.87-1.78 (2H, m).

Example 604-N-cyclobutyl-6-[3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from[3-(trifluoromethyl)phenyl]boronic acid and6-chloro-4-N-cyclobutylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 309; ¹H NMR(400 MHz, CD₃OD) δ_(H) 7.68 (2H, d, J=8.5 Hz), 7.14 (2H, d, J=8.5 Hz),6.22 (1H, s), 4.64 (1H, q, J=7.9 Hz), 3.90 (3H, s), 2.46-2.38 (2H, m),2.12-2.01 (2H, m), 1.87-1.78 (2H, m).

Example 61 6-(2,3-dichlorophenyl)-4-N-pentylpyrimidine-2,4-diamine

Prepared according to general procedure 3 from pentan-1-amine and4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 325; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.80-7.78 (1H, m), 7.52-7.50 (2H, m), 6.12(1H, s), 3.54-3.50 (2H, m), 1.69-1.65 (2H, m), 1.42-1.39 (4H, m),0.98-0.95 (3H, m).

Example 62 4-N-cyclopropyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from cyclopropanamine and4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 295; ¹HNMR (400 MHz, CDCl₃) δ_(H) 7.51 (1H, dd, J=7.9 and 1.6 Hz), 7.41 (1H,dd, J=7.9 and 1.6 Hz), 7.28 (1H, t, J=7.9 Hz), 6.35 (1H, s), 5.21 (1H,s), 4.78 (2H, s), 2.63-2.47 (1H, m), 0.86-0.78 (2H, m), 0.64-0.57 (2H,m).

Example 63 4-N-tert-butyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from 2-methylpropan-2-amineand 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 311.

Example 64 4-N-cyclobutyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from cyclobutanamine and4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 309; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.60-7.58 (1H, m), 7.37-7.34 (2H, m), 5.89(1H, s), 4.46 (1H, s), 3.37 (2H, s), 2.43-2.35 (2H, m), 2.01-1.94 (2H,m), 1.80-1.72 (2H, m).

Example 65 4-N-cyclopentyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from cyclopentanamine and4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 323; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.62-7.56 (1H, m), 7.40-7.34 (2H, m), 5.93(1H, s), 3.37 (1H, s), 2.09-1.98 (2H, m), 1.82-1.72 (2H, m), 1.71-1.61(2H, m), 1.58-1.48 (2H, m).

Example 66 6-(2,3-dichlorophenyl)-4-N-ethylpyrimidine-2,4-diamine

Prepared according to general procedure 3 from ethanamine and4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 283; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.62-7.57 (1H, m), 7.40-7.35 (2H, m), 5.92(1H, s), 3.44-3.36 (2H, m), 1.24 (3H, t, J=7.1 Hz).

Example 676-(2,3-dichlorophenyl)-4-N-(oxolan-3-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from oxolan-3-amine and4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 325; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.63-7.58 (1H, m), 7.39-7.35 (2H, m), 5.98(1H, s), 4.59 (1H, s), 4.02-3.94 (2H, m), 3.90-3.82 (1H, m), 3.73-3.67(1H, m), 2.36-2.26 (1H, m), 1.99-1.89 (1H, m).

Example 68 6-(3,4-dichlorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from(3,4-dichlorophenyl)boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 269; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.96 (1H, d, J=2.0 Hz), 7.77 (1H, d, J=8.5 Hz),7.70-7.55 (2H, m), 6.35 (1H, s), 3.06 (3H, s).

Example 69 6-(4-tert-butylphenyl)-4-N-methyl pyrimidine-2,4-diamine

Prepared according to general procedure 5 from(4-tert-butylphenyl)boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 257; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.77 (2H, d, J=8.7 Hz), 7.53-7.48 (2H, m), 6.22 (1H,s), 2.93 (3H, s), 1.38 (9H, s).

Example 70 4-N-methyl-6-(4-methylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 5 from (4-methylphenyl)boronicacid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 215; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.73 (2H, d, J=8.9 Hz), 7.28 (2H, d, J=8.9Hz), 6.20 (1H, s), 2.93 (3H, s), 2.41 (3H, s).

Example 71 6-(2,4-dichlorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 5 from(2,4-dichlorophenyl)boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 269; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.57 (1H, d, J=1.9 Hz), 7.48-7.41 (2H, m), 5.98 (1H,s), 2.92 (3H, s).

Example 72 4-N-methyl-6-(2,4,5-trifluorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 5 from(2,4,5-trifluorophenyl)boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 255; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.86-7.75 (1H, m), 7.31-7.24 (1H, m), 6.25 (1H, s),2.91 (3H, s).

Example 73 6-(4-fluoro-2-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 5 from(4-fluoro-2-methoxyphenyl)-boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 249; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.57 (1H, dd, J=8.5 and 6.3 Hz), 6.89 (1H, dd, J=11.4and 2.5 Hz), 6.76 (1H, td, J=8.5 and 2.5 Hz), 6.19 (1H, s), 3.87 (3H,s), 2.90 (3H, s).

Example 74 6-(5-chloro-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 5 from(5-chloro-2-methylphenyl)-boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 249; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.33-7.23 (3H, m), 5.85 (1H, s), 2.92 (3H, s), 2.32(3H, s).

Example 75 6-(2,4-difluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 5 from(2,4-difluorophenyl)boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 237; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.88-7.79 (1H, m), 7.10-7.00 (2H, m), 6.19 (1H, d,J=2.0 Hz), 2.92 (3H, s).

Example 76 6-(5-fluoro-2-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 5 from(5-fluoro-2-methoxyphenyl)-boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 249; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.36 (1H, dd, J=9.4 and 3.1 Hz), 7.15-7.04 (2H, m),6.28 (1H, s), 3.85 (3H, s), 2.91 (3H, s).

Example 77 6-(2-chlorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 5 from (2-chlorophenyl)boronicacid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 235; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.51-7.44 (1H, m), 7.42-7.36 (2H, m), 5.98(1H, s), 2.92 (3H, s).

Example 78 4-N-methyl-6-(pyridin-2-yl)pyrimidine-2,4-diamine

To a solution of 6-iodo-4-N-methylpyrimidine-2,4-diamine (1 eq.) and2-(tributylstannyl)pyridine (1.3 eq.) in toluene (1 mL) were added CuI(0.25 eq.) and Pd(PPh₃)₄ (0.05 eq.). The reaction mixture was heated at120° C. for 1 hour. The crude mixture was purified by HPLC. LCMS [M+H]⁺202.

Example 79 6-(4-methoxy-3-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(4-methoxy-3-methylphenyl)-boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 245; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.72-7.62 (2H, m), 6.99 (1H, d, J=8.3 Hz), 6.18 (1H,s), 3.91 (3H, s), 2.94 (3H, s), 2.28 (3H, s).

Example 80 6-(3-chloro-4-fluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(3-chloro-4-fluorophenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 253; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.05-7.99 (1H, m), 7.87-7.79 (1H, m), 7.33 (1H, t,J=8.2 Hz), 6.23 (1H, s), 2.94 (3H, s).

Example 814-N-methyl-6-[4-(trifluoromethoxy)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 6 from[4-(trifluoromethoxy)phenyl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 285; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.98-7.92 (2H, m), 7.38-7.32 (2H, m), 6.23 (1H, s),2.93 (3H, s).

Example 82 6-(3-fluoro-4-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(3-fluoro-4-methoxyphenyl)-boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 249; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.97-7.60 (2H, m), 7.21-7.12 (1H, m), 6.20 (1H, s),3.95 (3H, s), 2.94 (3H, s).

Example 83 6-(3,4-difluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(3,4-difluorophenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 237; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.86-7.77 (1H, m), 7.74-7.66 (1H, m), 7.40-7.30 (1H,m), 6.23 (1H, s), 2.94 (3H, s).

Example 84 4-N-methyl-6-[4-(propan-2-yloxy)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 6 from[4-(propan-2-yloxy)phenyl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 259.

Example 856-[2-fluoro-3-(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from[2-fluoro-3-(trifluoromethyl)phenyl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 287; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.98 (1H, t, J=7.0 Hz), 7.87 (1H, t, J=7.0 Hz), 7.52(1H, t, J=8.0 Hz), 6.27 (1H, d, J=1.5 Hz), 3.00 (3H, s).

Example 86 6-(2,3-dimethylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(2,3-dimethylphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 229; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.24-7.18 (1H, m), 7.17-7.05 (2H, m), 5.82 (1H, s),2.92 (3H, s), 2.35 (3H, s), 2.22 (3H, s).

Example 87 6-(3-chloro-2-fluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(3-chloro-2-fluorophenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 253; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.71-7.65 (1H, m), 7.58-7.53 (1H, m), 7.30-7.22 (1H,m), 6.18 (1H, d, J=2.1 Hz), 2.93 (3H, s).

Example 88 6-(4-chloro-3-fluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(4-chloro-3-fluorophenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 253; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.73-7.65 (2H, m), 7.62-7.55 (1H, m), 6.34 (1H, s),3.03 (3H, s).

Example 894-N-methyl-6-[2-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 6 from[2-(trifluoromethyl)-phenyl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 269; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.80 (1H, d, J=8.1 Hz), 7.70 (1H, t, J=7.7 Hz), 7.61(1H, t, J=7.7 Hz), 7.48 (1H, d, J=8.1 Hz), 5.88 (1H, s), 2.92 (3H, s).

Example 90 4-N-methyl-6-(1-methyl-1H-indazol-4-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 6 from(1-methyl-1H-indazol-4-yl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 255; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.42 (1H, s), 7.69-7.63 (1H, m), 7.60-7.50 (2H, m),6.33 (1H, s), 4.14 (3H, s), 2.97 (3H, s).

Example 916-[2-chloro-3-(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from[2-chloro-3-(trifluoromethyl)phenyl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 303; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.90-7.85 (1H, m), 7.71-7.66 (1H, m), 7.62-7.55 (1H,m), 5.95 (1H, s), 2.94 (3H, s).

Example 92 6-(2-chloro-3-fluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(2-chloro-3-fluorophenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 253; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.46-7.38 (1H, m), 7.35-7.28 (2H, m), 5.98 (1H, s),2.93 (3H, s).

Example 93 6-(2,3-difluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(2,3-difluorophenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 237; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.58-7.51 (1H, m), 7.34-7.31 (1H, m), 7.29-7.22 (1H,m), 6.20 (1H, s), 2.93 (3H, s).

Example 94 6-(3-chloro-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(3-chloro-2-methylphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 249; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.47-7.41 (1H, m), 7.27-7.21 (2H, m), 5.85 (1H, s),2.93 (3H, s), 2.36 (3H, s).

Example 95 6-(2,3-dichlorophenyl)-4-N,5-dimethylpyrimidine-2,4-diamine

Step 1: 4-chloro-6-(2,3-dichlorophenyl)-5-methylpyrimidin-2-amine wasprepared according to general procedure 2 from4,6-dichloro-5-methylpyrimidin-2-amine and (2,3-dichlorophenyl)boronicacid (and using DMF instead of dioxane).

Step 2: 6-(2,3-dichlorophenyl)-4-N,5-dimethylpyrimidine-2,4-diamine wasprepared according to general procedure 3 from methanamine and4-chloro-6-(2,3-dichlorophenyl)-5-methylpyrimidin-2-amine (prepared instep 1 above). LCMS [M+H]⁺ 283; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.62 (1H,dd, J=7.9 and 1.9 Hz), 7.41 (1H, t, J=7.9 Hz), 7.27 (1H, dd, J=7.9 and1.9 Hz), 3.01 (3H, s), 1.71 (3H, s).

Example 964-N-cyclopropyl-6-(2,3-dichlorophenyl)-5-methylpyrimidine-2,4-diamine

Was prepared according to general procedure 3 from cyclopropanamine and4-chloro-6-(2,3-dichlorophenyl)-5-methylpyrimidin-2-amine (prepared inexample 95, step 1 above). LCMS [M+H]⁺ 309; ¹H NMR (400 MHz, CD₃OD)δ_(H) 7.83 (1H, dd, J=7.7 and 1.2 Hz), 7.56 (1H, t, J=7.8 Hz), 7.48 (1H,dd, J=7.8 and 1.2 Hz), 3.17-3.09 (1H, m), 1.79 (3H, s), 0.96-0.90 (2H,m), 0.82-0.75 (2H, m).

Example 976-(7-chloro-2H-1,3-benzodioxol-5-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(7-chloro-2H-1,3-benzodioxol-5-yl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 279; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.11 (1H, s), 7.04 (1H, s), 6.13 (2H, s), 6.10 (1H,s), 3.04 (3H, s).

Example 986-(2,3-dichloro-4-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Step 1: 4-chloro-6-(2,3-dichloro-5-methoxyphenyl)pyrimidin-2-amine wasprepared according to general procedure 2 from4,6-dichloropyrimidin-2-amine and 2,3-dichloro-4-methoxyphenyl)boronicacid.

Step 2: Prepared according to general procedure 3 from methanamine and4-chloro-6-(2,3-dichloro-5-methoxyphenyl)pyrimidin-2-amine (prepared instep 1 above). LCMS [M+H]⁺ 299; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.49 (1H,d, J=8.6 Hz), 7.24 (1H, d, J=8.6 Hz), 6.11 (1H, s), 4.01 (3H, s), 3.09(3H, s).

Example 996-(2,3-dichloro-5-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(2,3-dichloro-5-methoxyphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 299; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.38 (1H, d, J=2.9 Hz), 7.12 (1H, d, J=2.9 Hz), 6.13(1H, s), 3.88 (3H, s), 3.05 (3H, s).

Example 100 4-[2-amino-6-(methylamino)pyrimidin-4-yl]phenol

Prepared according to general procedure 6 from (4-hydroxyphenyl)boronicacid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 217; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.69 (2H, d, J=8.5 Hz), 6.85 (2H, d, J=8.5Hz), 6.15 (1H, s), 4.59 (1H, s), 2.93 (3H, s).

Example 101 {3-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}methanol

Prepared according to general procedure 6 from [3-(hydroxymethyl)phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS[M+H]⁺ 231; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.83 (1H, s), 7.76-7.70 (1H,m), 7.45-7.41 (2H, m), 6.22 (1H, s), 4.68 (2H, s), 2.92 (3H, s).

Example 102 4-[2-amino-6-(methylamino)pyrimidin-4-yl]benzoic acid

Prepared according to general procedure 6 from4-(dihydroxyboranyl)benzoic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 245.

Example 103 methyl 4-[2-amino-6-(methylamino)pyrimidin-4-yl]benzoate

Prepared according to general procedure 6 from[4-(methoxycarbonyl)-phenyl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 259; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.12-8.06 (2H, m), 7.95 (2H, d, J=8.2 Hz), 6.28 (1H,s), 3.94 (3H, s), 2.93 (3H, s).

Example 1046-[3-chloro-4-(morpholine-4-carbonyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from[3-chloro-4-(morpholine-4-carbonyl)phenyl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 348; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.90 (1H, d, J=1.8 Hz), 7.75 (1H, dd, J=7.9 and 1.8Hz), 7.59 (1H, d, J=7.9 Hz), 6.35 (1H, s), 3.85-3.74 (6H, m), 3.69-3.60(2H, m), 3.04 (3H, s).

Example 105 4-[2-amino-6-(methylamino)pyrimidin-4-yl]-2,3-dichlorophenol

Prepared according to general procedure 6 from2,3-dichloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and6-iodo-4-N-methylpyrimidine-2,4-diamine.

LCMS [M+H]⁺ 285; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.32 (1H, d, J=8.7 Hz),7.04 (1H, d, J=8.7 Hz), 6.09 (1H, s), 3.04 (3H, s).

Example 106 methyl(2E)-3-{4-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}prop-2-enoate

Prepared according to general procedure 6 from{4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]phenyl}boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 285; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.82 (4H, s), 7.76 (1H, d, J=16.0 Hz), 6.69 (1H, d,J=16.0 Hz), 6.36 (1H, s), 3.83 (3H, s), 3.04 (3H, s).

Example 107 methyl(2E)-3-{3-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}prop-2-enoate

Prepared according to general procedure 6 from{3-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]phenyl}boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 285; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.99-7.95 (1H, m), 7.92-7.86 (1H, m), 7.83-7.73 (2H,m), 7.69-7.63 (1H, m), 6.72 (1H, d, J=16.0 Hz), 6.37 (1H, s), 3.83 (3H,s), 3.07 (3H, s).

Example 108 4-[2-amino-6-(methylamino)pyrimidin-4-yl]benzaldehyde

Prepared according to general procedure 6 from (4-formylphenyl)boronicacid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 229.

Example 109 1-(4-(2-Amino-6-(methylamino)pyrimidin-4-yl)phenyl)ethanone

Prepared according to general procedure 6 from (4-acetylphenyl)boronicacid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 243; ¹HNMR (400 MHz, CD₃OD) δ_(H) 8.22-8.15 (2H, m), 7.88-7.82 (2H, m), 6.38(1H, s), 3.05 (3H, s), 2.67 (3H, s).

Example 110 4-[2-amino-6-(methylamino)pyrimidin-4-yl]-N-methylbenzamide

Prepared according to general procedure 6 from[4-(methylcarbamoyl)phenyl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 258; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.02 (2H, d, J=8.5 Hz), 7.83 (2H, d, J=8.5 Hz), 6.38(1H, s), 3.06 (3H, s), 2.97 (3H, s).

Example 111 6-(4-ethenylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (4-ethenylphenyl)boronicacid and 6-iodo-4-N-methylpyrimidine-2,4-diamine.

LCMS [M+H]⁺ 227; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.75-7.63 (4H, m), 6.84(1H, dd, J=17.5 and 10.7 Hz), 6.34 (1H, s), 5.98 (1H, d, J=17.5 Hz),5.43 (1H, d, J=10.7 Hz), 3.06 (3H, s).

Example 1126-(2,3-dimethylphenyl)-4-N-[2-(piperidin-1-yl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 7 from2-(piperidin-1-yl)ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 326.

Example 1136-(2,3-dimethylphenyl)-4-N-[2-(morpholin-4-yl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 7 from2-(morpholin-4-yl)ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 328.

Example 114 4-N-cyclopropyl-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from(2,3-dimethylphenyl)boronic acid and6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 255; ¹H NMR(400 MHz, CD₃OD) δ_(H) 7.42-7.31 (1H, m), 7.29-7.12 (2H, m), 6.44 (0.3H,s), 5.95 (0.7H, s), 3.13. (0.7H, s), 2.68 (0.3H, s), 2.36 (3H, s), 2.25(3H, s), 0.95-0.79 (2H, m), 0.72-0.55 (2H, m).

Example 1153-[2-amino-6-(methylamino)pyrimidin-4-yl]-N-(4-methylphenyl)benzamide

Step 1: A mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (48 mg,0.30 mmol), 3-(dihydroxyboranyl)benzoic acid (60 mg, 0.36 mmol), K₂CO₃(104 mg, 0.75 mmol) and palladium tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol) in 1,4-dioxane (3 mL) and water (1 mL) washeated in a sealed tube at 90° C. for 15 h. Concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 245.

Step 2: To a mixture of 3-(2-amino-6-(methylamino)pyrimidin-4-yl)benzoicacid (50 mg, 0.47 mmol) and p-toluidine (150 mg, 1.4 mmol) in DMF (2.5mL) were added HATU (266 mg, 0.70 mmol) and NEt₃ (200 μL, 1.4 mmol). Themixture was stirred at rt overnight. The crude reaction mixture waspurified by HPLC. LCMS [M+H]⁺ 334.

Example 116 6-(1H-indol-3-yl)-4-N-methylpyrimidine-2,4-diamine

To a solution of4-N-methyl-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine(1 eq.; prepared in example 23) in MeOH (2 mL) was added 10% NaOH (1mL). The reaction mixture was heated at 50° C. overnight and the crudeproduct was purified by HPLC. LCMS [M+H]⁺ 240; ¹H NMR (400 MHz, CD₃OD)δ_(H) 8.04 (1H, d, J=7.7 Hz), 7.82 (1H, s), 7.46-7.36 (1H, m), 7.21-7.09(2H, m), 6.29 (1H, s), 2.92 (3H, s).

Example 117 6-phenyl-4-N-(2-phenylethyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from phenylboronic acid and6-chloro-4-N-(2-phenylethyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 291; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.83-7.73 (2H, m), 7.47-7.37 (3H, m),7.31-7.22 (4H, m), 7.21-7.15 (1H, m), 6.17 (1H, s), 3.60 (2H, t, J=7.3Hz), 2.91 (2H, t, J=7.3 Hz).

Example 1186-(2,3-dimethylphenyl)-4-N-(2-phenylethyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from(2,3-dimethylphenyl)boronic acid and6-chloro-4-N-(2-phenylethyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 319; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.31-7.23 (4H, m), 7.21-7.15 (2H, m), 7.10(1H, t, J=7.0 Hz), 7.05 (1H, d, J=7.0 Hz), 5.77 (1H, s), 3.64-3.50 (2H,m), 2.90 (2H, t, J=7.6 Hz), 2.31 (3H, s), 2.19 (3H, s).

Example 1196-(3-chlorophenyl)-4-N-(2,2-difluoroethyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (3-chlorophenyl)boronicacid and 6-chloro-4-N-(2,2-difluoroethyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 285.

Example 1206-(3-chloro-2-methoxypyridin-4-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from(3-chloro-2-methoxypyridin-4-yl)boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 266.

Example 121

4-(2,3-dimethylphenyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-2-amine. To asolution of 4-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-amine(10 mg, 0.054 mmol, 1 eq.) in DMF/water (9:1) is added2,3-dimethylphenylboronic acid (8.9 mg, 0.060 mmol, 1.1 eq.), Na₂CO₃(11.5 mg, 0.11 mmol, 2 eq.) and Pd(PPh₃)₄ (3.1 mg, 0.002 mmol, 0.05eq.). The mixture is heated at 120° C. in a microwave reactor until thereaction is complete as shown by LCMS. The crude mixture is thenpurified by HPLC to afford the desired product. LCMS [M+H]⁺ 255; ¹H NMR(400 MHz, DMSO-d₆) δ_(H) 12.05 (1H, br s), 8.88 (1H, br s), 7.37 (1H, d,J=6.9 Hz), 7.29 (1H, t, J=7.6 Hz), 7.17 (1H, d, J=6.3 Hz), 3.34-3.32(2H, m), 2.32 (3H, s), 2.28-2.26 (2H, m), 2.09 (3H, s), 1.76-1.74 (2H,m).

Example 1224-(2,3-dichlorophenyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-2-amine

To a solution of4-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-amine (10 mg, 0.054mmol, 1 eq.) in DMF/water (9:1) is added 2,3-dichlorophenylboronic acid(11.3 mg, 0.060 mmol, 1.1 eq.), Na₂CO₃ (11.5 mg, 0.11 mmol, 2 eq.) andPd(PPh₃)₄ (3.1 mg, 0.002 mmol, 0.05 eq.). The mixture is heated at 120°C. in a microwave reactor until the reaction is complete as shown byLCMS. The crude mixture is then purified by HPLC to afford the desiredproduct. LCMS [M+H]⁺ 295.

Example 1234-[1-(benzenesulfonyl)-1H-indol-3-yl]-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-2-amine

To a solution of4-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-amine (10 mg, 0.054mmol, 1 eq.) in DMF/water (9:1) is added(1-(phenylsulfonyl)-1H-indol-3-yl)boronic acid (18.0 mg, 0.060 mmol, 1.1eq.), Na₂CO₃ (11.5 mg, 0.11 mmol, 2 eq.) and Pd(PPh₃)₄ (3.1 mg, 0.002mmol, 0.05 eq.). The mixture is heated at 120° C. in a microwave reactoruntil the reaction is complete as shown by LCMS. The crude mixture isthen purified by HPLC to afford the desired product. LCMS [M+H]⁺ 406; ¹HNMR (400 MHz, DMSO-d₆) δ_(H) 12.03 (1H, br s), 8.03 (1H, br s), 8.36(1H, s), 8.09 (2H, dd, J=8.6 Hz and 1.2 Hz), 8.04 (1H, d, J=8.3 Hz),7.78-7.76 (1H, m), 7.68-7.66 (2H, m), 7.61 (1H, d, J=7.8 Hz), 7.48 (1H,ddd, J=8.4 Hz, 7.3 Hz and 1.1 Hz), 7.38 (1H, ddd, J=8.0 Hz, 7.2 Hz and1.0 Hz), 3.38-3.36 (2H, m), 2.48-2.46 (2H, m), 1.76-1.74 (2H, m).

Example 124 6-(3,5-difluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from(3,5-difluorophenyl)boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 237.

Example 1256-(2,3-dimethylphenyl)-4-N-[2-(4-methoxyphenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 7 from2-(4-methoxyphenyl)ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 349.

Example 1266-(2,3-dimethylphenyl)-4-N-[2-(2-methoxyphenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 7 from2-(2-methoxyphenyl)ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 349.

Example 1276-(2,3-dimethylphenyl)-4-N-[2-(4-methylphenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 7 from2-(4-methylphenyl)ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 333.

Example 1284-N-[2-(4-chlorophenyl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 7 from2-(4-chlorophenyl)ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 353.

Example 1296-(2,3-dimethylphenyl)-4-N-[2-(pyridin-2-yl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 7 from2-(pyridin-2-yl)ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 320.

Example 1306-(2,3-dimethylphenyl)-4-N-(2-phenylpropyl)pyrimidine-2,4-diamine

Prepared according to general procedure 7 from 2-phenylpropan-1-amineand 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 333.

Example 1316-(2,3-dimethylphenyl)-4-N-(3-phenylpropyl)pyrimidine-2,4-diamine

Prepared according to general procedure 7 from 3-phenylpropan-1-amineand 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 333.

Example 1326-(2,3-dimethylphenyl)-4-N-(2-phenoxyethyl)pyrimidine-2,4-diamine

Prepared according to general procedure 7 from (2-aminoethoxy)benzeneand 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 335.

Example 1336-(2,3-dimethylphenyl)-4-N-[2-(phenylamino)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 7 from N-(2-aminoethyl)anilineand 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 334.

Example 1346-(2,3-dimethylphenyl)-4-N-[2-(1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 7 from2-(1H-indol-3-yl)ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 358.

Example 135 6-(2,3-dimethylphenyl)-4-N-pentylpyrimidine-2,4-diamine

Prepared according to general procedure 7 from pentan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 285.

Example 1361-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)imidazolidin-2-one

Prepared according to general procedure 7 from1-(2-aminoethyl)imidazolidin-2-one and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 327.

Example 1371-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

Prepared according to general procedure 7 from1-(3-aminopropyl)pyrrolidin-2-one and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 340.

Example 138 4-[2-amino-6-(methylamino)pyrimidin-4-yl]-2,6-dimethylphenol

Prepared according to general procedure 6 from(4-hydroxy-3,5-dimethylphenyl)boronic acid. LCMS [M+H]⁺ 245; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.44 (2H, s), 6.12 (1H, s), 2.91 (3H, s), 2.27 (6H,s).

Example 139 4-[2-amino-6-(methylamino)pyrimidin-4-yl]-2-methoxyphenol

Prepared according to general procedure 6 from(4-hydroxy-3-methoxyphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 247; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.46 (1H, s), 7.33 (1H, d, J=8.4 Hz), 6.86 (1H, d,J=8.0 Hz), 6.17 (1H, s), 3.34 (3H, s), 2.92 (3H, s).

Example 140 4-[2-amino-6-(methylamino)pyrimidin-4-yl]-2-fluorophenol

Prepared according to general procedure 6 from(3-fluoro-4-hydroxyphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 235.

Example 141 5-[2-amino-6-(methylamino)pyrimidin-4-yl]pyridin-2-ol

Prepared according to general procedure 6 from(6-hydroxypyridin-3-yl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 218; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.99 (1H, s), 7.86 (1H, d, J=9.6 Hz), 6.68 (1H, dd,J=9.6 and 0.4 Hz), 6.21 (1H, s), 3.04 (3H, s).

Example 142 {4-[2-amino-6-(methylamino)pyri midi n-4-yl]phenyl}methanol

Prepared according to general procedure 6 from[4-(hydroxymethyl)phenyl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 231; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.79 (2H, d, J=8.0 Hz), 7.43 (2H, d, J=8.4 Hz), 6.21(1H, s), 4.65 (2H, s), 2.91 (3H, s).

Example 143 4-N-methyl-6-(2-methylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2-methylphenyl)boronicacid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 215; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.29-7.23 (4H, m), 5.83 (1H, s), 2.90 (3H,s), 2.33 (3H, s).

Example 1446-[1-(4-chlorobenzenesulfonyl)-1H-indol-3-yl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(4-chlorobenzenesulfonyl)-1H-indol-3-yl]boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 414; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.15 (1H, s), 8.08 (1H, d, J=8.0 Hz), 8.04 (1H, d,J=8.0 Hz), 8.00-7.98 (2H, m), 7.57-7.55 (2H, m), 7.41 (1H, td, J=8.4 and1.2 Hz), 7.35 (1H, td, J=8.0 and 0.8 Hz), 6.28 (1H, s), 2.29 (3H, s).

Example 1454-N-methyl-6-(4-methyl-1H-indazol-5-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 6 from(4-methyl-1H-indazol-5-yl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 255.

Example 1464-N-methyl-6-(6-methyl-1H-indazol-5-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 6 from(6-methyl-1H-indazol-5-yl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 255; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.12 (1H, d, J=0.8 Hz), 7.88 (1H, s), 7.56 (1H, d,J=0.8 Hz), 6.09 (1H, s), 3.07 (3H, s), 2.50 (3H, d, J=0.8 Hz).

Example 147 4-N-methyl-6-(3-methylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 6 from (3-methylphenyl)boronicacid. LCMS [M+H]⁺ 215; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.56 (1H, s),7.51-7.47 (3H, m), 6.32 (1H, s), 3.06 (3H, s), 2.47 (3H, s).

Example 148 6-(1H-indol-5-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (1H-indol-5-yl)boronicacid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 240; ¹HNMR (400 MHz, CD₃OD) δ_(H) 8.00 (1H, dd, J=1.6 and 0.4 Hz), 7.59 (1H,td, J=8.4 and 0.8 Hz), 7.47 (1H, dd, J=8.4 and 1.6 Hz), 7.42 (1H, d,J=3.2 Hz), 6.63 (1H, dd, J=3.2 and 1.2 Hz), 6.35 (1H, s), 3.06 (3H, s).

Example 149 6-(3-chloropyridin-4-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(3-chloropyridin-4-yl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 236; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.83 (1H, s), 8.71 (1H, d, J=5.2 Hz), 7.62 (1H, d,J=4.8 Hz), 6.24 (1H, s), 3.07 (3H, s).

Example 150{5-[2-amino-6-(methylamino)pyrimidin-4-yl]pyridin-2-yl}methanol

Prepared according to general procedure 6 from[6-(hydroxymethyl)pyridin-3-yl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 232.

Example 151 4-N-cyclobutyl-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from(2,3-dimethylphenyl)boronic acid and6-chloro-4-N-cyclobutylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 269; ¹H NMR(400 MHz, CD₃OD) δ_(H) 7.20 (1H, d, J=7.2 Hz), 7.13 (1H, t, J=7.2 Hz),7.08 (1H, d, J=7.2 Hz), 5.77 (1H, s), 4.44 (1H, br s), 2.44-2.36 (2H,m), 2.34 (3H, s), 2.21 (3H, s), 2.04-1.94 (m, 2H), 1.82-1.73 (m, 2H).

Example 1524-N-cyclobutyl-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and6-chloro-4-N-cyclobutylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 434; ¹H NMR(400 MHz, CD₃OD) δ_(H) 8.39 (1H, s), 8.09 (1H, d, J=8.4 Hz), 7.96-7.94(2H, m), 7.84 (1H, d, J=8.0 Hz), 7.50 (1H, td, J=7.2 and 0.8 Hz), 7.35(1H, td, J=7.2 and 0.8 Hz), 7.41-7.39 (2H, m), 6.44 (1H, s), 4.66 (1H,quintet, J=8.4 Hz), 2.47-2.41 (2H, m), 2.39 (3H, s), 2.14-2.04 (2H, m),1.89-1.82 (2H, m).

Example 153 4-N-cyclopentyl-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from(2,3-dimethylphenyl)boronic acid and6-chloro-4-N-cyclopentylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 283; ¹H NMR(400 MHz, CD₃OD) δ_(H) 7.19 (1H, d, J=7.2 Hz), 7.13 (1H, t, J=7.6 Hz),7.08 (1H, dd, J=7.6 and 1.6 Hz), 5.81 (1H, s), 4.25 (1H, br s), 2.33(3H, s), 2.22 (3H, s), 2.06-2.00 (2H, m), 1.81-1.74 (2H, m), 1.71-1.63(2H, m), 1.58-1.51 (2H, m).

Example 1544-N-cyclopentyl-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and6-chloro-4-N-cyclopentylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 448; ¹H NMR(400 MHz, CD₃OD) δ_(H) 8.38 (1H, s), 8.10 (1H, d, J=8.4 Hz), 7.96-7.94(2H, m), 7.84 (1H, d, J=8.0 Hz), 7.50 (1H, td, J=7.2 and 1.2 Hz), 7.42(1H, td, J=7.2 and 0.8 Hz), 7.41-7.39 (2H, m), 6.48 (1H, s), 4.51 (1H,quintet, J=6.8 Hz), 2.39 (3H, s), 2.14-2.05 (2H, m), 1.84-1.78 (2H, m),1.75-1.66 (2H, m), 1.63-1.57 (2H, m).

Example 1554-N-methyl-6-{1-[4-(trifluoromethyl)benzenesulfonyl]-1H-indol-3-yl}pyrimidine-2,4-diamine

Prepared according to general procedure 8 from{1-[4-(trifluoromethyl)benzenesulfonyl]-1H-indol-3-yl}boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 448; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.19 (2H, d, J=8.4 Hz), 8.16 (1H, s), 8.08-8.04 (2H,m), 7.84 (2H, d, J=8.4 Hz), 7.41 (1H, td, J=7.6 and 0.8 Hz), 7.34 (1H,td, J=8.0 and 0.8 Hz), 6.26 (1H, s), 2.92 (s, 3H).

Example 156 4-N-cyclohexyl-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from(2,3-dimethylphenyl)boronic acid and6-chloro-4-N-cyclohexylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 297; ¹H NMR(400 MHz, CD₃OD) δ_(H) 7.19 (1H, d, J=7.2 Hz), 7.12 (1H, t, J=7.6 Hz),7.08 (1H, dd, J=7.6 and 1.6 Hz), 5.78 (1H, s), 3.82 (1H, br s), 2.33(3H, s), 2.21 (3H, s), 2.03-1.99 (2H, m), 1.83-1.78 (2H, m), 1.71-1.66(1H, m), 1.48-1.37 (2H, m), 1.31-1.21 (3H, m).

Example 1574-N-cyclohexyl-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and6-chloro-4-N-cyclohexylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 462; ¹H NMR(400 MHz, CD₃OD) δ_(H) 8.36 (1H, s), 8.08 (1H, d, J=8.0 Hz), 7.95-7.93(2H, m), 7.83 (1H, d, J=8.0 Hz), 7.48 (1H, td, J=7.2 and 0.8 Hz), 7.41(1H, td, J=8.0 and 1.2 Hz), 7.40-7.38 (2H, m), 6.46 (1H, s), 4.11-4.05(1H, m), 2.38 (3H, s), 2.04-2.00 (2H, m), 1.86-1.82 (2H, m), 1.72-1.68(1H, m), 1.48-1.26 (5H, m).

Example 158 6-(2,3-dimethylphenyl)-4-N-ethylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from(2,3-dimethylphenyl)boronic acid and6-chloro-4-N-ethylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 243; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.19 (1H, d, J=7.2 Hz), 7.13 (1H, t, J=7.6 Hz), 7.08(1H, dd, J=7.6 and 1.2 Hz), 5.80 (1H, s), 3.41-3.36 (2H, m), 2.33 (3H,s), 2.21 (3H, s), 1.23 (3H, t, J=7.2 Hz).

Example 159 4-N-ethyl-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and6-chloro-4-N-ethylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 408; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.12 (1H, s), 8.05-8.01 (2H, m), 7.87-7.85 (2H, m),7.37 (1H, td, J=7.2 and 1.2 Hz), 7.34-7.32 (2H, m), 7.30 (1H, td, J=8.0and 1.2 Hz), 6.26 (1H, s), 3.39 (2H, q, J=7.2 Hz), 2.34 (3H, s), 1.24(3H, t, J=7.2 Hz).

Example 160 4-N-tert-butyl-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from(2,3-dimethylphenyl)boronic acid and4-N-tert-butyl-6-chloropyrimidine-2,4-diamine. LCMS [M+H]⁺ 271; ¹H NMR(400 MHz, CD₃OD) δ_(H) 7.18 (1H, d, J=7.2 Hz), 7.12 (1H, t, J=7.6 Hz),7.07 (1H, dd, J=7.6 and 1.6 Hz), 5.81 (1H, s), 2.33 (3H, s), 2.21 (3H,s), 1.49 (9H, s).

Example 1614-N-tert-butyl-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and4-N-tert-butyl-6-chloropyrimidine-2,4-diamine. LCMS [M+H]⁺ 436; ¹H NMR(400 MHz, CD₃OD) δ_(H) 8.36 (1H, s), 8.08 (1H, d, J=8.4 Hz), 7.95-7.93(2H, m), 7.84 (1H, d, J=7.6 Hz), 7.48 (1H, td, J=7.2 and 1.2 Hz), 7.40(1H, td, J=8.4 and 1.2 Hz), 7.40-7.38 (2H, m), 6.52 (1H, s), 2.38 (3H,s), 1.54 (9H, s).

Example 1626-(2,3-dimethylphenyl)-4-N-(propan-2-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 (2,3-dimethylphenyl)boronicacid and 6-chloro-4-N-(propan-2-yl)pyrimidine-2,4-diamine. LCMS [M+H]⁺257; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.36 (1H, d, J=7.2 Hz), 7.25 (1H, t,J=7.6 Hz), 7.19 (1H, d, J=7.2 Hz), 5.96 (1H, s), 4.39 (1H, septet, J=6.4Hz), 2.37 (3H, s), 2.26 (3H, s), 1.29 (3H, s), 1.27 (3H, s).

Example 1636-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]-4-N-(propan-2-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and6-chloro-4-N-(propan-2-yl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 422; ¹HNMR (400 MHz, CD₃OD) δ_(H) 8.12 (1H, s), 8.05-8.02 (2H, m), 7.89-7.86(2H, m), 7.40-7.30 (4H, m), 6.25 (1H, s), 4.19 (1H, br s), 2.36 (3H, s),1.26 (3H, s), 1.24 (3H, s).

Example 1644-N-(cyclopropylmethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from(2,3-dimethylphenyl)boronic acid and6-chloro-4-N-(cyclopropylmethyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 269.

Example 1654-N-(cyclopropylmethyl)-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and6-chloro-4-N-(cyclopropylmethyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 434;¹H NMR (400 MHz, CD₃OD) δ_(H) 8.14 (1H, s), 8.06-8.02 (2H, m), 7.88-7.86(2H, m), 7.40-7.30 (5H, m), 6.31 (1H, s), 3.25 (2H, d, J=6.8 Hz),1.14-1.11 (1H, m), 0.57-0.55 (2H, m), 0.30-0.28 (2H, m).

Example 166 4-N-[(1R)-1-cyclopropylethyl]-6-(2, 3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from(2,3-dimethylphenyl)boronic acid and6-chloro-4-N-[(1R)-1-cyclopropylethyl]pyrimidine-2,4-diamine. LCMS[M+H]⁺ 283; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.19 (1H, d, J=6.8 Hz), 7.13(1H, t, J=7.6 Hz), 7.09 (1H, dd, J=7.6 and 1.2 Hz), 5.80 (1H, s), 3.58(1H, br s), 2.34 (3H, s), 2.22 (3H, s), 1.28 (3H, d, J=6.4 Hz),0.99-0.92 (1H, m), 0.57-0.45 (2H, m), 0.44-0.38 (1H, m), 0.29-0.23 (1H,m).

Example 1674-N-[(1R)-1-cyclopropylethyl]-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and6-chloro-4-N-[(1R)-1-cyclopropylethyl]pyrimidine-2,4-diamine. LCMS[M+H]⁺ 448; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.37 (1H, s), 8.08 (1H, d,J=8.0 Hz), 7.95-7.93 (2H, m), 7.84 (1H, d, J=7.6 Hz), 7.49 (1H, dt,J=7.6 and 1.2 Hz), 7.42 (1H, dt, J=8.0 and 0.8 Hz), 7.40-7.38 (2H, m),6.47 (1H, s), 3.78-3.71 (1H, m), 2.38 (3H, s), 1.33 (3H, d, J=6.8 Hz),1.04-0.99 (1H, m), 0.64-0.57 (1H, m), 0.56-0.49 (1H, m), 0.47-0.41 (1H,m), 0.33-0.27 (1H, m).

Example 1684-N-[(1S)-1-cyclopropylethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from(2,3-dimethylphenyl)boronic acid and6-chloro-4-N-[(1S)-1-cyclopropylethyl]pyrimidine-2,4-diamine. LCMS[M+H]⁺ 283; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.18 (1H, d, J=6.8 Hz), 7.11(1H, t, J=7.6 Hz), 7.07 (1H, dd, J=7.6 and 1.6 Hz), 5.78 (1H, s), 3.56(1H, br s), 2.32 (3H, s), 2.20 (3H, s), 1.27 (3H, d, J=6.4 Hz),0.98-0.91 (1H, m), 0.56-0.43 (2H, m), 0.42-0.36 (1H, m), 0.27-0.21 (1H,m).

Example 169 4-N-[(1S)-1-cyclopropylethyl]-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and6-chloro-4-N-[(1S)-1-cyclopropylethyl]pyrimidine-2,4-diamine. LCMS[M+H]⁺ 448; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.37 (1H, s), 8.09 (1H, d,J=8.4 Hz), 7.96-7.94 (2H, m), 7.85 (1H, d, J=8.0 Hz), 7.49 (1H, dt,J=7.6 and 1.2 Hz), 7.42 (1H, dt, J=8.0 and 1.2 Hz), 7.41-7.39 (2H, m),6.47 (1H, s), 3.78-3.71 (1H, m), 2.39 (3H, s), 1.33 (3H, d, J=6.8 Hz),1.05-0.98 (1H, m), 0.63-0.58 (1H, m), 0.57-0.50 (1H, m), 0.48-0.42 (1H,m), 0.33-0.27 (1H, m).

Example 170 6-(1-benzofuran-3-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(1-benzofuran-3-yl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 241; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.27 (1H, s), 8.07 (1H, dd, J=8.0 and 1.2 Hz),7.58-7.56 (1H, m), 7.35 (2H, dt, J=7.6 and 1.2 Hz), 6.32 (1H, s), 2.95(3H, s).

Example 171 6-(2-chloro-5-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from(2-chloro-5-methylphenyl)boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 249; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.35 (1H, d, J=8.0 Hz), 7.28 (1H, d, J=2.0 Hz),7.23-7.20 (1H, m), 5.97 (1H, s), 2.92 (3H, s), 2.38 (3H, s).

Example 172 6-(1-benzothiophen-3-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from(1-benzothiophen-3-yl)boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 257; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.27 (1H, d, J=7.2 Hz), 7.97-7.94 (1H, m), 7.92 (1H,s), 7.45 (1H, dt, J=7.2 and 1.6 Hz), 7.41 (1H, dt, J=7.2 and 1.6 Hz),6.20 (1H, s), 2.95 (3H, s).

Example 1732-{4-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}propan-2-ol

Prepared according to general procedure 2 from[4-(2-hydroxypropan-2-yl)phenyl]boronic acid and6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 259; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.82-7.80 (2H, m), 7.60-7.57 (2H, m), 6.23 (1H, s),2.94 (3H, s), 1.58 (6H, s).

Example 174 6-(1H-indol-4-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (1H-indol-4-yl)boronicacid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 240; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.50-7.48 (1H, m), 7.38 (1H, dd, J=7.6 and0.8 Hz), 7.34 (1H, d, J=3.2 Hz), 7.21 (1H, t, J=7.6 Hz), 6.80 (1H, dd,J=3.2 and 0.8 Hz), 6.31 (1H, s), 2.96 (3H, s).

Example 175 4-N-cyclohexyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from cyclohexanamine and4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 337; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.63-7.61 (1H, m), 7.40 (1H, d, J=2.0 Hz),7.39 (1H, s), 5.93 (1H, s), 3.88 (1H, br s), 2.06-2.02 (2H, m),1.86-1.81 (2H, m), 1.73-1.69 (1H, m), 1.50-1.40 (2H, m), 1.34-1.25 (3H,m).

Example 1766-(2,3-dichlorophenyl)-4-N-(propan-2-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from propan-2-amine and4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 297; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.61-7.59 (1H, m), 7.38 (1H, d, J=2.0 Hz),7.37 (1H, s), 5.92 (1H, s), 4.17 (1H, br s), 1.25 (3H, s), 1.24 (3H, s).

Example 1774-N-(cyclopropylmethyl)-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from cyclopropylmethanamineand 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 309.

Example 1784-N-[(1S)-1-cyclopropylethyl]-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from(1S)-1-cyclopropylethan-1-amine and4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 323; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.61-7.59 (1H, m), 7.38 (1H, d, J=2.0 Hz),7.37 (1H, s), 5.92 (1H, s), 3.59 (1H, br s), 1.28 (3H, d, J=6.8 Hz),0.99-0.92 (2H, m), 0.53-0.48 (2H, m), 0.46-0.38 (1H, m), 0.29-0.23 (1H,m).

Example 1794-N-[(1R)-1-cyclopropylethyl]-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from(1R)-1-cyclopropylethan-1-amine and4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 323; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.61-7.59 (1H, m), 7.38 (1H, d, J=2.0 Hz),7.37 (1H, s), 5.92 (1H, s), 3.59 (1H, br s), 1.28 (3H, d, J=6.8 Hz),0.99-0.92 (2H, m), 0.58-0.47 (2H, m), 0.46-0.38 (1H, m), 0.29-0.23 (1H,m).

Example 1806-(2,3-dichlorophenyl)-4-N-(2,2-dimethylpropyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from2,2-dimethylpropan-1-amine and4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 325; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.61-7.58 (1H, m), 7.38 (1H, d, J=2.0 Hz),7.36 (1H, s), 6.01 (1H, s), 3.27 (2H, br s), 0.98 (9H, s).

Example 1816-(2,3-dimethylphenyl)-4-N-(2,2-dimethylpropyl)pyrimidine-2,4-diamine

Prepared according to general procedure 5 from(2,3-dimethylphenyl)boronic acid and6-chloro-4-N-(2,2-dimethylpropyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺285; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.20 (1H, d, J=6.8 Hz), 7.14 (1H, t,J=7.6 Hz), 7.10 (1H, dd, J=7.6 and 1.6 Hz), 5.90 (1H, s), 2.34 (3H, s),2.22 (3H, s), 1.00 (9H, s).

Example 1824-N-(2,2-dimethylpropyl)-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and6-chloro-4-N-(2,2-dimethylpropyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺450; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.14 (1H, s), 8.08 (1H, d, J=7.6),8.04 (1H, dt, J=8.0 and 1.2 Hz), 7.90-7.88 (2H, m), 7.39 (1H, td, J=7.2and 1.2 Hz), 7.37-7.34 (2H, m), 7.33 (1H, td, J=7.2 and 1.2 Hz), 6.38(1H, s), 3.27 (2H, s), 2.37 (3H, s), 1.02 (9H, s).

Example 183 6-(5-bromo-2-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(5-bromo-2-methoxyphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 310; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.72 (1H, d, J=2.4 Hz), 7.52 (1H, dd, J=8.8 and 2.8Hz), 7.04 (1H, d, J=9.2 Hz), 6.25 (1H, s), 3.87 (3H, s), 2.91 (s, 3H).

Example 184 6-(2,5-dimethylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(2,5-dimethylphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 229; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.16-7.13 (2H, m), 7.11 (1H, s), 5.84 (1H, s), 2.92(3H, s), 2.35 (3H, s), 2.29 (3H, s).

Example 1854-N-methyl-6-[2-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 6 from[2-(trifluoromethyl)pyridin-3-yl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 270.

Example 186 4-N-methyl-6-(pyrimidin-5-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 6 from (pyrimidin-5-yl)boronicacid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 203.

Example 187

6-[4-(benzyloxy)-2-methylphenyl]-4-N-methylpyrimidine-2,4-diamine.

Prepared according to general procedure 6 from[4-(benzyloxy)-2-methylphenyl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 321; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.47-7.46 (2H, m), 7.41-7.38 (2H, m), 7.35-7.32 (1H,m), 7.24 (1H, d, J=8.4 Hz), 6.92-6.87 (2H, m), 5.84 (1H, s), 5.14 (2H,s), 2.91 (3H, s), 2.34 (3H, s).

Example 1886-(4-methoxy-2,5-dimethylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(4-methoxy-2,5-dimethylphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 259; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.08 (1H, s), 6.79 (1H, s), 5.83 (1H, s), 3.86 (3H,s), 2.91 (3H, s), 2.34 (3H, s), 2.19 (3H, s).

Example 189 4-N-methyl-6-(2,4,5-trimethyl phenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 6 from(2,4,5-trimethylphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 243; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.07 (1H, s), 7.03 (1H, s), 5.83 (1H, s), 2.91 (3H,s), 2.28 (9H, s).

Example 1902-[2-amino-6-(methylamino)pyrimidin-4-yl]-4-chlorobenzonitrile

Prepared according to general procedure 6 from(5-chloro-2-cyanophenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 260.

Example 1916-(4,5-dichloro-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(4,5-dichloro-2-methylphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 283; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.62 (1H, s), 7.61 (1H, s), 6.06 (1H, s), 3.04 (3H,s), 2.36 (3H, s).

Example 1926-(2,5-dichloro-4-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(2,5-dichloro-4-methoxyphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 299; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.52 (1H, s), 7.22 (1H, s), 6.03 (1H, s), 3.96 (3H,s), 2.92 (3H, s).

Example 1936-(4-fluoro-2,5-dimethylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(4-fluoro-2,5-dimethylphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 247; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.16 (1H, d, J=8.0 Hz), 6.95 (1H, d, J=10.8 Hz), 5.83(1H, s), 2.91 (3H, s), 2.30 (3H, s), 2.27 (3H, s).

Example 1944-N-methyl-6-[2-methyl-5-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 6 from[2-methyl-5-(trifluoromethyl)phenyl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 283; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.78-7.73 (2H, m), 7.61 (1H, d, J=8.0 Hz), 6.08 (1H,s), 3.05 (3H, s), 2.46 (3H, s).

Example 1956-[5-chloro-2-methyl-4-(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from[5-chloro-2-methyl-4-(trifluoromethyl)phenyl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 317; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.69 (1H, s), 7.53 (1H, s), 5.89 (1H, s), 2.93 (3H,s), 2.40 (3H, s).

Example 1966-[2,5-bis(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from[2,5-bis(trifluoromethyl)phenyl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 337; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.20-8.15 (2H, m), 8.10 (1H, s), 6.15 (1H, s), 3.08(3H, s).

Example 1976-(5-tert-butyl-2-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(5-tert-butyl-2-methoxyphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 287; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.64 (1H, dd, J=8.8 and 2.4 Hz), 7.51 (1H, s), 7.17(1H, d, J=8.8 Hz), 6.25 (1H, s), 3.94 (3H, s), 3.05 (3H, s), 1.37 (9H,s).

Example 1986-[2-methoxy-5-(propan-2-yl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from[2-methoxy-5-(propan-2-yl)phenyl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 273; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.49 (1H, dd, J=8.4 and 2.0 Hz), 7.39 (1H, s), 7.17(1H, d, J=8.8 Hz), 6.28 (1H, s), 3.95 (3H, s), 3.06 (3H, s), 2.98 (1H,sept, J=6.8 Hz), 1.31 (3H, s), 1.30 (3H, s).

Example 1996-[2-chloro-5-(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from[2-chloro-5-(trifluoromethyl)phenyl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 303; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.87 (1H, br s), 7.82 (1H, d, J=2.0 Hz), 7.81 (1H, s),6.14 (1H, s), 3.03 (3H, s).

Example 200 6-(2-fluoro-5-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(2-fluoro-5-methylphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 233; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.58 (1H, dd, J=7.2 and 2.0 Hz), 7.28-7.25 (1H, m),7.10-7.06 (1H, m), 6.02 (1H, d, J=1.6 Hz), 2.94 (3H, s), 2.40 (3H, s).

Example 2016-(5-chloro-2-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(5-chloro-2-methoxyphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 265; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.58-7.57 (1H, m), 7.56 (1H, d, J=2.8 Hz), 7.23 (1H,d, J=9.6 Hz), 6.27 (1H, s), 3.96 (3H, s), 3.05 (3H, s).

Example 202 6-(5-fluoro-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(5-fluoro-2-methylphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 233; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.31-7.27 (1H, m), 7.08-7.04 (2H, m), 5.87 (1H, s),2.94 (3H, s), 2.33 (3H, s).

Example 203 6-(2,5-dimethoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(2,5-dimethoxyphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 261; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.18 (1H, d, J=3.2 Hz), 7.04 (1H, d, J=9.2 Hz), 6.98(1H, dd, J=8.8 and 3.2 Hz), 6.27 (1H, s), 3.83 (6H, s), 2.93 (3H, s).

Example 2046-(2-methoxy-5-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(2-methoxy-5-methylphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 245; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.36 (1H, s), 7.20 (1H, d, J=8.8 Hz), 6.98 (1H, d,J=8.8 Hz), 6.20 (1H, s), 3.83 (3H, s), 2.91 (3H, s), 2.33 (3H, s).

Example 205 6-(2-chloro-5-fluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(2-chloro-5-fluorophenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 253; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.54-7.50 (1H, m), 7.25 (1H, dd, J=9.2 and 3.2 Hz),7.19 (1H, td, J=8.8 and 3.2 Hz), 6.01 (1H, s), 2.93 (3H, s).

Example 2063-[2-amino-6-(methylamino)pyrimidin-4-yl]-4-fluorobenzonitrile

Prepared according to general procedure 6 from(5-cyano-2-fluorophenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 244; ¹H NMR (400MHz, CD₃OD) δ_(H) 8.26 (1H, dd, J=6.8 and 2.0 Hz), 7.87-7.84 (1H, m),7.45-7.40 (1H, m), 6.27 (1H, d, J=2.0 Hz), 2.93 (3H, s).

Example 2076-(2-chloro-5-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(2-chloro-5-methoxyphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 265; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.39 (1H, d, J=8.8 Hz), 7.02 (1H, d, J=3.2 Hz), 6.98(1H, dd, J=8.8 and 3.2 Hz), 5.99 (1H, s), 3.84 (3H, s), 2.92 (3H, s).

Example 2086-[5-fluoro-2-(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from[5-fluoro-2-(trifluoromethyl)phenyl]boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 287; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.87-7.83 (1H, m), 7.39-7.34 (1H, m), 7.25 (1H, dd,J=9.2 and 2.8 Hz), 5.89 (1H, s), 2.92 (3H, s).

Example 209 6-(2,5-dichlorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(2,5-dichlorophenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 269; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.51-7.49 (2H, m), 7.42 (1H, dd, J=8.4 and 2.4 Hz),6.01 (1H, s), 2.92 (3H, s).

Example 210 6-(5-chloro-2-fluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(5-chloro-2-fluorophenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 253; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.75-7.23 (1H, m), 7.69-7.65 (1H, m), 7.40 (1H, m),6.31 (1H, s), 3.07 (3H, s).

Example 2113-[2-amino-6-(methylamino)pyrimidin-4-yl]-4-methylbenzonitrile

Prepared according to general procedure 6 from(5-cyano-2-methylphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 240; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.68-7.66 (2H, m), 7.48 (1H, d, J=7.6 Hz), 5.88 (1H,s), 2.93 (3H, s), 2.44 (3H, s).

Example 2123-[2-amino-6-(methylamino)pyrimidin-4-yl]-4-methoxybenzonitrile

Prepared according to general procedure 6 from(5-cyano-2-methoxyphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 256; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.95 (1H, d, J=2.4 Hz), 7.98 (1H, dd, J=8.8 and 2.0Hz), 7.27 (1H, d, J=8.8 Hz), 6.26 (1H, s), 3.97 (3H, s), 2.92 (3H, s).

Example 2136-(2-chloro-5-fluoro-4-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(2-chloro-5-fluoro-4-methylphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 267; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.39 (1H, d, J=6.8 Hz), 7.19 (1H, d, J=9.6 Hz), 6.02(1H, s), 2.92 (3H, s), 2.32 (3H, d, J=1.6 Hz).

Example 2146-(5-chloro-2-fluoro-4-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(5-chloro-2-fluoro-4-methylphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 267; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.72 (1H, d, J=6.8 Hz), 7.19 (1H, d, J=11.2 Hz), 6.31(1H, s), 3.05 (3H, s), 2.48 (3H, s).

Example 2156-(2-chloro-4-fluoro-5-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(2-chloro-4-fluoro-5-methylphenyl)boronic acid. and6-iodo-4-N-methylpyrimidine-2,4-diamine LCMS [M+H]⁺ 267; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.36 (1H, d, J=8.4 Hz), 7.23 (1H, d, J=9.6 Hz), 5.96(1H, s), 2.91 (3H, s), 2.29 (3H, d, J=1.6 Hz).

Example 2164-N-cyclopropyl-6-(4-fluoro-2,5-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from(4-fluoro-2,5-dimethylphenyl)boronic acid and6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 273; ¹H NMR(400 MHz, CD₃OD) δ_(H) 7.19 (1H, d, J=8.0 Hz), 6.97 (1H, d, J=10.4 Hz),6.03 (1H, s), 2.63 (1H, br s), 2.33 (3H, s), 2.28 (3H, s), 0.84-0.79(2H, m), 0.60-0.56 (2H, m).

Example 217

4-N-cyclopropyl-6-(4-methoxy-2,5-dimethylphenyl)pyrimidine-2,4-diamine.

Prepared according to general procedure 2 from(4-methoxy-2,5-dimethylphenyl)boronic acid and6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 285.

Example 218 4-N-cyclopropyl-6-(2,5-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from(2,5-dimethylphenyl)boronic acid and6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 255; ¹H NMR(400 MHz, CD₃OD) δ_(H) 7.30-7.28 (2H, m), 7.23 (1H, s), 6.00 (1H, s),3.06 (1H, br s), 2.40 (3H, s), 2.36 (3H, s), 0.93-0.88 (2H, m),0.69-0.66 (2H, m).

Example 2196-(5-chloro-2-methylphenyl)-4-N-cyclopropylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from(5-chloro-2-methylphenyl)boronic acid and6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 275; ¹H NMR(400 MHz, CD₃OD) δ_(H) 7.33-7.27 (3H, m), 6.05 (1H, s), 2.65 (1H, br s),0.84-0.79 (2H, m), 0.60-0.56 (2H, m).

Example 2206-(5-chloro-2-methylphenyl)-4-N-cyclobutylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from(5-chloro-2-methylphenyl)boronic acid and6-chloro-4-N-cyclobutylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 289; ¹H NMR(400 MHz, CD₃OD) δ_(H) 7.33-7.26 (3H, m), 5.81 (1H, s), 4.45 (1H, br s),2.44-2.37 (2H, m), 2.32 (3H, s), 2.05-1.95 (2H, m), 1.83-1.74 (2H, m).

Example 221 6-(5-chloro-2-methylphenyl)-4-N-ethylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from(5-chloro-2-methylphenyl)boronic acid and6-chloro-4-N-ethylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 263; ¹H NMR (400MHz, CD₃OD) δ_(H) 7.51-7.46 (2H, m), 7.41 (1H, d, J=8.4 Hz), 6.05 (1H,s), 3.57 (2H, q, J=6.8 Hz), 2.37 (3H, s), 1.28 (3H, t, J=7.2 Hz).

Example 222

6-(5-chloro-2-methylphenyl)-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine.

Prepared according to general procedure 2 from(5-chloro-2-methylphenyl)boronic acid and6-chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine. LCMS[M+H]⁺ 374; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.32-7.26 (7H, m), 5.81 (1H,s), 3.64-3.60 (2H, m), 2.92 (2H, t, J=7.6 Hz), 2.31 (3H, s).

Example 2234-N-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-2,5-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from(4-fluoro-2,5-dimethylphenyl)boronic acid and6-chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine. LCMS[M+H]⁺ 371; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.32-7.26 (4H, m), 7.14 (1H,d, J=8.0 Hz), 6.94 (1H, d, J=10.8 Hz), 5.79 (1H, s), 3.63-3.59 (2H, m),2.92 (2H, t, J=7.2 Hz), 2.30 (3H, s), 2.27 (3H, s).

Example 2244-N-[2-(4-chlorophenyl)ethyl]-6-(2,5-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from(2,5-dimethylphenyl)boronic acid and6-chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine. LCMS[M+H]⁺ 353; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.32-7.26 (4H, m), 7.16-7.09(3H, m), 5.80 (1H, s), 3.61 (2H, t, J=6.4 Hz), 2.92 (2H, t, J=7.2 Hz),2.35 (3H, s), 2.28 (3H, s).

Example 2251-(3-{[2-amino-6-(quinolin-5-yl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

Prepared according to general procedure 2 from (quinolin-5-yl)boronicacid and1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one.LCMS [M+H]⁺ 363; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.90 (1H, dd, J=4.0 and1.6 Hz), 8.64 (1H, d, J=8.8 Hz), 8.12 (1H, d, J=8.4 Hz), 7.88-7.84 (1H,m), 7.71 (1H, d, J=7.2 Hz), 7.59-7.56 (1H, m), 6.07 (1H, s), 3.53 (2H,t, J=6.8 Hz), 3.42 (4H, t, J=6.8 Hz), 2.42 (2H, t, J=8.0 Hz), 2.12-2.05(2H, m), 1.93-1.86 (2H, m).

Example 226 6-(2-chloro-3-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 3 from methanamine and4-chloro-6-(2-chloro-3-methylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 249;¹H NMR (400 MHz, CD₃OD) δ_(H) 7.56-7.54 (1H, m), 7.42-7.37 (2H, m), 6.11(1H, s), 3.05 (3H, s), 2.49 (3H, s).

Example 2276-(2-chloro-3-methylphenyl)-4-N-cyclopropylpyrimidine-2,4-diamine

Prepared according to general procedure 3 from cyclopropanamine and4-chloro-6-(2-chloro-3-methylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 275;¹H NMR (400 MHz, CD₃OD) δ_(H) 7.56 (1H, d, J=5.6 Hz), 7.42-7.39 (2H, m),6.07 (1H, s), 3.09 (1H, br s), 2.50 (3H, s), 0.92-0.90 (2H, m), 0.68(2H, br s).

Example 2286-(2-chloro-3-methylphenyl)-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 3 from2-(4-chlorophenyl)ethan-1-amine and4-chloro-6-(2-chloro-3-methylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 373;¹H NMR (400 MHz, CD₃OD) δ_(H) 7.57-7.55 (1H, m), 7.41 (1H, t, J=7.6 Hz),7.37 (1H, dd, J=8.0 and 2.0 Hz), 7.34-7.28 (4H, m), 6.08 (1H, s), 3.79(2H, t, J=7.2 Hz), 2.97 (2H, t, J=7.2 Hz), 2.49 (3H, s).

Example 2291-(3-{[2-amino-6-(2-chloro-3-methylphenyl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

Prepared according to general procedure 3 from1-(3-aminopropyl)pyrrolidin-2-one and4-chloro-6-(2-chloro-3-methylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 360;¹H NMR (400 MHz, CD₃OD) δ_(H) 7.57-7.55 (1H, m), 7.44-7.38 (2H, m), 6.13(1H, s), 3.55 (2H, t, J=5.6 Hz), 3.52 (2H, t, J=7.2 Hz), 3.41 (2H, t,J=6.8 Hz), 2.49 (3H, s), 2.42 (2H, t, J=8.0 Hz), 2.09 (2H, quintet,J=7.6 Hz), 1.92 (2H, quintet, J=7.2 Hz).

Example 230 4-N-cyclopropyl-6-(1H-indol-4-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from cyclopropanamine and4-chloro-6-(1H-indol-4-yl)pyrimidin-2-amine. LCMS [M+H]⁺ 266; ¹H NMR(400 MHz, CD₃OD) δ_(H) 7.67 (1H, d, J=7.6 Hz), 7.50 (1H, s), 7.33 (2H,d, J=7.2 Hz), 6.71 (1H, s), 6.43 (1H, s), 3.10 (1H, br s), 0.92 (2H, brs), 0.69 (2H, br s).

Example 2314-N-[2-(4-chlorophenyl)ethyl]-6-(1H-indol-4-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from2-(4-chlorophenyl)ethan-1-amine and4-chloro-6-(1H-indol-4-yl)pyrimidin-2-amine. LCMS [M+H]⁺ 364; ¹H NMR(400 MHz, CD₃OD) δ_(H) 7.67-7.66 (1H, m), 7.52-7.46 (1H, m), 7.35-7.29(6H, m), 6.86 (1H, s), 6.44 (1H, s), 3.80 (2H, t, J=7.2 Hz), 2.95 (2H,t, J=6.8 Hz).

Example 232 4-N-cyclopropyl-6-(quinolin-5-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from cyclopropanamine and4-chloro-6-(quinolin-5-yl)pyrimidin-2-amine. LCMS [M+H]⁺ 278; ¹H NMR(400 MHz, CD₃OD) δ_(H) 8.91 (1H, dd, J=4 and 1.6 Hz), 8.66 (1H, d, J=8.4Hz), 8.14 (1H, d, J=8.4 Hz), 7.89-7.85 (1H, m), 7.74 (1H, d, J=6.8 Hz),7.59-7.56 (1H, m), 6.26 (1H, s), 2.69 (1H, br s), 0.85-0.80 (2H, m),0.62-0.59 (2H, m).

Example 233(2E)-3-{4-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}prop-2-enoicacid

Prepared according to general procedure 6 from(2E)-3-[4-(dihydroxyboranyl)phenyl]prop-2-enoic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 271.

Example 234 tert-butyl3-({[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}methyl)-azetidine-1-carboxylate

Prepared according to general procedure 3 from tert-butyl3-(aminomethyl)azetidine-1-carboxylate and4-chloro-6-(2,3-dimethylphenyl)-pyrimidin-2-amine. LCMS [M+H]⁺ 384; ¹HNMR (400 MHz, CD₃OD) δ_(H) 7.19 (1H, d, J=7.6 Hz), 7.12 (1H, t, J=7.6Hz), 7.07 (1H, d, J=7.6 Hz), 5.82 (s, 1H), 4.05-4.00 (2H, m), 3.73-3.69(2H, m), 3.60-3.59 (2H, m), 2.92-2.82 (1H, m), 2.33 (3H, s), 2.21 (3H,s), 1.45 (9H, s).

Example 235 4-N-cyclopropyl-6-(1H-indol-5-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (1H-indol-5-yl)boronicacid and 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺266.

Example 2361-(3-{[2-amino-6-(1H-indol-5-yl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

Prepared according to general procedure 2 from(2,3-dimethylphenyl)boronic acid and1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one.LCMS [M+H]⁺ 351; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.02 (1H, d, J=1.6 Hz),7.59 (1H, d, J=8.4 Hz), 7.48 (1H, dd, J=8.4 and 2.0 Hz), 7.42 (1H, d,J=3.2 Hz), 6.64 (1H, d, J=3.2 Hz), 6.37 (1H, s), 3.57-3.51 (4H, m), 3.42(2H, t, J=7.2 Hz), 2.43 (2H, t, J=8.0 Hz), 2.10 (2H, quintet, J=8.4 Hz),1.93 (2H, quintet, J=7.2 Hz).

Example 237 tert-Butyl4-((2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl)amino)piperidine-1-carboxylate

Prepared according to general procedure 3 from4-chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine and tert-butyl4-aminopiperidine-1-carboxylate. LCMS [M+H]⁺ 398; ¹H NMR (400 MHz,CD₃OD) δ_(H) 7.19 (1H, d, J=6.8 Hz), 7.13 (1H, t, J=7.6 Hz), 7.08 (1H,dd, J=7.2 and 0.8 Hz), 5.82 (1H, s), 4.07-4.05 (2H, m), 2.99 (2H, m),2.33 (3H, s), 2.22 (3H, s), 2.03-1.99 (2H, s), 1.49 (9H, s), 1.42-1.39(2H, m).

Example 238 Ethyl4-((2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl)amino)piperidine-1-carboxylate

Prepared according to general procedure 3 from4-chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine and ethyl4-aminopiperidine-1-carboxylate. LCMS [M+H]⁺ 370; ¹H NMR (400 MHz,CD₃OD) δ_(H) 7.19 (1H, d, J=7.2 Hz), 7.11 (1H, t, J=7.2 Hz), 7.08 (1H,d, J=7.6 Hz), 5.82 (1H, s), 4.15 (2H, q, J=7.2 Hz), 4.15-4.09 (3H, m),3.07-2.98 (2H, m), 2.33 (3H, s), 2.21 (3H, s), 2.04-2.01 (2H, m),1.48-1.39 (2H, m), 1.29 (4H, t, J=7.2 Hz).

Example 239 tert-Butyl(3-((2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl)amino)-2,2-dimethyl-propyl)carbamate

Prepared according to general procedure 3 from4-chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine and tert-butylN-(3-amino-2,2-dimethylpropyl)carbamate. LCMS [M+H]⁺ 400.

Example 2406-(5-chloro-4-methoxy-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from(5-chloro-4-methoxy-2-methylphenyl)boronic acid and6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 279.

Example 2416-(3-chloro-2-methylphenyl)-4-N-[(1R)-1-phenylethyl]pyrimidine-2,4-diamine

4-Chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (25 mg, 0,098mmol) and (+)1-phenylethan-1-amine (0.050 mL) were stirred neat at 150°C. for 1 hour. The crude material was dissolved in MeOH (2 mL) andpurified by preparative HPLC to give the desired product. LCMS [M+H]⁺339; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 9.25 (1H, d, J=8.08 Hz)7.62-7.71 (1H, m) 7.24-7.47 (7H, m) 6.23 (0.1H, s) 6.09 (0.9H, s) 5.35(1H, quin, J=7.26 Hz) 2.31 (2.7H, s) 2.13 (0.3H, s) 1.46-1.57 (3H, m).

Example 2426-(3-chloro-2-methylphenyl)-4-N-(2-phenylpropan-2-yl)pyrimidine-2,4-diamine

4-Chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (25 mg, 0,098mmol) and 2-phenylpropan-2-amine (0.050 mL) were stirred neat at 150° C.for 24 hours. The crude material was dissolved in MeOH (2 mL) andpurified by preparative HPLC to give the desired product. LCMS [M+H]⁺353; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 12.45 (1H, br. s.) 8.96 (1H,br. s.) 7.12-7.79 (8H, m) 6.22 (1H, s) 2.31 (3H, s) 1.79 (6H, br. s.)

Example 2436-(3-chloro-2-methylphenyl)-4-N-[1-(1H-indol-3-yl)propan-2-yl]pyrimidine-2,4-diamine

4-Chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (25 mg, 0,098mmol) and 1-(1H-indol-3-yl)propan-2-amine (0.050 mL) were stirred neatat 150° C. for 1 hour. The crude material was dissolved in MeOH (2 mL)and purified by preparative HPLC to give the desired product. LCMS[M+H]⁺ 392; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 12.34 (1H, br. s.) 10.90(0.9H, s) 10.85 (0.1H, br. s.) 8.79 (0.9H, d, J=7.83 Hz) 8.63 (0.1H, d,J=9.09 Hz) 7.66 (0.9H, dd, J=7.20, 2.15 Hz) 7.62 (0.1H, d, J=7.58 Hz)7.54 (1H, d, J=7.83 Hz) 7.28-7.43 (3H, m) 7.20 (0.9H, d, J=2.27 Hz)6.95-7.13 (2H, m) 6.89-6.95 (0.1H, m) 5.99 (0.9H, s) 5.93 (0.1H, s)4.39-4.50 (1H, m) 2.86-3.03 (2H, m) 2.30 (2.7H, s) 2.14 (0.3H, s) 1.27(0.3H, d, J=6.32 Hz) 1.20 (2.7H, d, J=6.57 Hz).

Example 2444-N-{bicyclo[2.2.1]heptan-2-yl}-6-(3-chloro-2-methylphenyl)pyrimidine-2,4-diamine

4-Chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (25 mg, 0,098mmol) and bicyclo[2.2.1]heptan-2-amine (0.050 mL) were stirred neat at150° C. for 1 hour. The crude material was dissolved in MeOH (˜2 mL) andpurified by preparative HPLC to give the desired product. LCMS [M+H]⁺329; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 8.66 (1H, br. s.) 7.62-7.69(1H, m) 7.35-7.44 (2H, m) 5.99 (1H, s) 3.87 (1H, br. s.) 2.30 (3H, s)2.27-2.35 (1H, m) 2.24 (1H, d, J=3.28 Hz) 1.70-1.80 (1H, m) 1.33-1.60(4H, m) 1.09-1.26 (3H, m)

Example 245 6-(3-chloro-2-methylphenyl)-4-N-ethylpyrimidine-2,4-diamine

4-Chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (25 mg, 0,098mmol), 70% ethanamine (0.050 mL) and n-butanol (2 mL) were stirred in asealed tube at 120° C. for 8 hours. The solvent was removed in vacuo andthe crude material was dissolved in MeOH (2 mL) and purified bypreparative HPLC to give the desired product. LCMS [M+H]⁺ 263; ¹H NMR(400 MHz, DMSO-d₆) δ_(H) ppm 12.49 (1H, br. s.) 8.86 (0.9H, t, J=5.18Hz) 8.63-8.73 (0.1H, m) 7.60-7.70 (1H, m) 7.34-7.45 (2H, m) 6.34 (0.1H,br. s.) 6.02 (0.9H, s) 3.23-3.58 (2H, m) 2.33 (0.3H, s) 2.30 (2.7H, s)1.18 (2.7H, t, J=7.20 Hz) 1.08-1.14 (0.3H, m)

Example 2466-(3-chloro-2-methylphenyl)-4-N-(propan-2-yl)pyrimidine-2,4-diamine

4-Chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (25 mg, 0,098mmol), propan-2-amine (0.050 mL) and n-butanol (2 mL) were stirred in asealed tube at 120° C. for 8 hours. The solvent was removed in vacuo andthe crude material was dissolved in MeOH (2 mL) and purified bypreparative HPLC to give the desired product. LCMS [M+H]⁺ 277.

Example 2474-N-[2-(2-chlorophenoxy)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

4-Chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (13 mg, 0,054 mmol) and1-(2-aminoethoxy)-2-chlorobenzene (18 mg, 0.11 mmol) were stirred neatat 150° C. for 1 h. The crude material was dissolved in MeOH (1 mL) andpurified by preparative HPLC to give the desired product. LCMS [M+H]⁺369

Example 2484-N-[2-(5-chloro-1H-1,3-benzodiazol-2-yl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

4-Chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (23 mg, 0.10mmol), 2-(5-chloro-1H-1,3-benzodiazol-2-yl)ethan-1-amine (20 mg, 0.10mmol), Et₃N (0.040 mL, 0.30 mmol) and 1-butanol (0.20 mL) were stirredat 100° C. for 20 hours.

MeOH (1 mL) was added and the mixture was purified by preparative HPLCto give the desired product. LCMS [M+H]⁺ 393.

Example 2494-N-[2-(2,5-dimethyl-1H-indol-3-yl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

4-Chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (12 mg, 0,050 mmol) and2-(2,5-dimethyl-1H-indol-3-yl)ethan-1-amine (0.020 mL) were stirred neatat 150° C. for 1 hour. The crude material was dissolved in MeOH (1 mL)and purified by preparative HPLC to give the desired product. LCMS[M+H]⁺ 386; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.30 (1H, br. s.) 10.65(0.9H, s) 10.60 (0.1H, s) 8.82 (0.9H, t, J=5.56 Hz) 8.56-8.67 (0.1H, m)7.06-7.41 (5H, m) 6.70-6.85 (1H, m) 5.97 (0.9H, s) 5.76 (0.1H, s) 3.58(1.8H, q, J=6.65 Hz) 3.48 (0.2H, d, J=6.32 Hz) 2.93 (0.8H, t, J=7.07 Hz)2.80-2.89 (0.2H, m) 2.23-2.38 (9H, m) 2.17 (2.7H, s) 2.06 (0.3H, s)

Example 2506-(2,3-dimethylphenyl)-4-N-[2-(pyridin-3-yloxy)propyl]pyrimidine-2,4-diamine

4-Chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (12 mg, 0,050 mmol) and3-[(1-aminopropan-2-yl)oxy]pyridine (15 mg, 0.10 mmol) were stirred neatat 150° C. for 1 h. The crude material was dissolved in MeOH (1 mL) andpurified by preparative HPLC to give the desired product. LCMS [M+H]⁺350.

Example 2516-(2,3-dimethylphenyl)-4-N-(1H-indazol-5-ylmethyl)pyrimidine-2,4-diamine

4-Chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (12 mg, 0,050 mmol),1H-indazol-5-ylmethanamine (15 mg, 0.10 mmol), Et₃N (0.040 mL, 0.30mmol) and 1-butanol (0.20 mL) were stirred at 100° C. for 20 hours. MeOH(1 mL) was added and the mixture was purified by preparative HPLC togive the desired product. LCMS [M+H]⁺ 345.

Example 2526-(2,3-dimethylphenyl)-4-N-(1H-indazol-6-ylmethyl)pyrimidine-2,4-diamine

4-Chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (12 mg, 0,050 mmol),1H-indazol-6-ylmethanamine (15 mg, 0.10 mmol), Et3N (0.040 mL), 0.30mmol) and 1-butanol (0.20 mL) were stirred at 100° C. for 20 h. MeOH (1mL) was added and the mixture was purified by preparative HPLC to givethe desired product. LCMS [M+H]⁺ 345

Example 2536-(2,3-dimethylphenyl)-4-N-[(2-methoxypyridin-4-yl)methyl]pyrimidine-2,4-diamine

4-Chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (12 mg, 0,050 mmol),(2-methoxypyridin-4-yl)methanamine (14 mg, 0.10 mmol), Et₃N (0.040 mL,0.30 mmol) and 1-butanol (0.20 mL) were stirred at 100° C. for 20 hours.MeOH (1 mL) was added and the mixture was purified by preparative HPLCto give the desired product. LCMS [M+H]⁺ 336.

Example 2544-N-[(5-chloropyrazin-2-yl)methyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

4-Chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (12 mg, 0,050 mmol),(5-chloropyrazin-2-yl)methanamine (14 mg, 0.10 mmol), Et₃N (0.040 mL,0.30 mmol) and 1-butanol (0.20 mL) were stirred at 100° C. for 20 hours.MeOH (1 mL) was added and the mixture was purified by preparative HPLCto give the desired product. LCMS [M+H]⁺ 341.

Example 2556-(2,3-dimethylphenyl)-4-N-{imidazo[1,2-a]pyridin-2-ylmethyl}pyrimidine-2,4-diamine

4-Chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (12 mg, 0,050 mmol),imidazo[1,2-a]pyridin-2-ylmethanamine (14 mg, 0.10 mmol), Et₃N (0.040mL, 0.30 mmol) and 1-butanol (0.20 mL) were stirred at 100° C. for 20hours. MeOH (1 mL) was added and the mixture was purified by preparativeHPLC to give the desired product. LCMS [M+H]⁺ 345.

Example 256

tert-butyl4-{4-[2-amino-6-(methylamino)pyrimidin-4-yl]-2-(methoxymethyl)phenoxymethyl}piperidine-1-carboxylate.

A mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (24 mg, 0.15mmol), tert-butyl4-[4-(dimethoxyboranyl)-2-(methoxymethyl)phenoxymethyl]piperidine-1-carboxylate(67 mg, 0.17 mmol), potassium carbonate (41 mg, 0.30 mmol) and palladiumtetrakis(triphenylphosphine)palladium (0) (9 mg, 0.008 mmol) in1,4-dioxane (5 mL) and water (1.5 mL) was heated in a sealed tube at 90°C. overnight. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 458.

Example 2576-[3-(methoxymethyl)-4-(piperidin-4-ylmethoxy)phenyl]-4-N-methylpyrimidine-2,4-diaminehydrochloride

A solution of tert-butyl4-{4-[2-amino-6-(methylamino)pyrimidin-4-yl]-2-(methoxymethyl)-phenoxymethyl}piperidine-1-carboxylate(45 mg, 0.10 mmol; Example 256) in methanol (3 mL) was treated with 4MHCl in 1,4-dioxane (1 mL). The mixture was stirred at r.t. for 3 h,concentrated and dried in vacuo to give the desired product. LCMS [M+H]⁺358.

Example 2583-[2-amino-6-(methylamino)pyrimidin-4-yl]-2-methylbenzonitrile

A mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (24 mg, 0.15mmol), (3-cyano-2-methylphenyl)boronic acid (29 mg, 0.18 mmol),potassium carbonate (41 mg, 0.30 mmol) and palladiumtetrakis(triphenylphosphine)palladium (0) (9 mg, 0.008 mmol) in1,4-dioxane (3 mL) and water (1 mL) was heated in a sealed tube at 90°C. overnight. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 240.

Example 2596-(4-methoxy-2,3-dimethylphenyl)-4-N-methylpyrimidine-2,4-diamine

A mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (24 mg, 0.15mmol), (4-methoxy-2,3-dimethylphenyl)boronic acid (32 mg, 0.18 mmol),potassium carbonate (41 mg, 0.30 mmol) andtetrakis(triphenylphosphine)palladium (0) (9 mg, 0.008 mmol) in1,4-dioxane (3 mL) and water (1 mL) was heated in a sealed tube at 90°C. overnight. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 259.

Example 2606-(4-fluoro-2,3-dimethylphenyl)-4-N-methylpyrimidine-2,4-diamine

A mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (24 mg, 0.15mmol), (4-fluoro-2,3-dimethylphenyl)boronic acid (30 mg, 0.18 mmol),potassium carbonate (41 mg, 0.30 mmol) andtetrakis(triphenylphosphine)palladium (0) (9 mg, 0.008 mmol) in1,4-dioxane (3 mL) and water (1 mL) was heated in a sealed tube at 90°C. overnight. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 247.

Example 2616-(2,3-dihydro-1-benzofuran-7-yl)-4-N-methylpyrimidine-2,4-diamine

A mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (24 mg, 0.15mmol), (2,3-dihydro-1-benzofuran-7-yl)boronic acid (30 mg, 0.18 mmol),potassium carbonate (41 mg, 0.30 mmol) andtetrakis(triphenylphosphine)palladium (0) (9 mg, 0.008 mmol) in1,4-dioxane (3 mL) and water (1 mL) was heated in a sealed tube at 90°C. overnight. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 243.

Example 2624-N-methyl-6-[2-methyl-5-(morpholine-4-sulfonyl)phenyl]pyrimidine-2,4-diamine

A mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (24 mg, 0.15mmol), [2-methyl-5-(morpholine-4-sulfonyl)phenyl]boronic acid (51 mg,0.18 mmol), potassium carbonate (41 mg, 0.30 mmol) andtetrakis(triphenylphosphine)-palladium (0) (9 mg, 0.008 mmol) in1,4-dioxane (3 mL) and water (1 mL) was heated in a sealed tube at 90°C. overnight. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 364.

Example 2634-N-[2-(4-chlorophenyl)ethyl]-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (28 mg,0.10 mmol), 2-(4-chlorophenyl)ethan-1-amine (22 mg, 0.14 mmol) andHünig's base (36 μL, 0.20 mmol) in n-butanol (2 mL) was heated in asealed tube at 85° C. overnight. The reaction mixture was concentratedand purified by preparative HPLC. LCMS [M+H]⁺ 393. 1H NMR (400 MHz,DMSO-d6) δ_(H) ppm 12.56 (br. s., 1H), 8.90 (br. s., 1H), 7.83-7.89 (m,1H), 7.51-7.59 (m, 2H), 7.35-7.41 (m, 2H), 7.28-7.34 (m, 2H), 6.11 (s,1H), 3.63 (q, J=6.4 Hz, 2H), 2.89 (t, J=7.1 Hz, 2H).

Example 2644-N-[2-(4-chlorophenyl)ethyl]-6-(2-methylphenyl)pyrimidine-2,4-diamine

A mixture of6-chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine (34 mg,0.12 mmol), (2-methylphenyl)boronic acid (20 mg, 0.14 mmol), potassiumcarbonate (33 mg, 0.24 mmol) and palladiumtetrakis(triphenylphosphine)-palladium (0) (7 mg, 0.006 mmol) in1,4-dioxane/water (4 mL; 4:1) was heated in a sealed tube at 90° C.overnight. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 339.

Example 2654-N-[2-(4-chlorophenyl)ethyl]-6-[3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

A mixture of6-chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine (34 mg,0.12 mmol), [3-(trifluoromethyl)phenyl]boronic acid (27 mg, 0.14 mmol),potassium carbonate (33 mg, 0.24 mmol) and palladiumtetrakis(triphenylphosphine)palladium (0) (7 mg, 0.006 mmol) in1,4-dioxane/water (4 mL; 4:1) was heated in a sealed tube at 90° C.overnight. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 393.

Example 2664-N-[2-(4-chlorophenyl)ethyl]-6-(quinolin-5-yl)pyrimidine-2,4-diamine

A mixture of6-chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine (34 mg,0.12 mmol), (quinolin-5-yl)boronic acid (25 mg, 0.14 mmol), potassiumcarbonate (33 mg, 0.24 mmol) and palladiumtetrakis(triphenylphosphine)palladium (0) (7 mg, 0.006 mmol) in1,4-dioxane/water (4 mL; 4:1) was heated in a sealed tube at 90° C.overnight. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 376.

Example 2674-N-[2-(4-chlorophenyl)cyclopropyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg,0.12 mmol), 2-(4-chlorophenyl)cyclopropan-1-amine (43 mg, 0.26 mmol) andHünig's base (90 μL, 0.52 mmol) in n-butanol (2 mL) was heated in asealed tube at 85° C. overnight. The reaction mixture was concentratedand purified by preparative HPLC. LCMS [M+H]⁺ 365.

Example 2686-(2,3-dimethylphenyl)-4-N-[2-(pyridin-3-yl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg,0.12 mmol), 2-(pyridin-3-yl)ethan-1-amine (21 mg, 0.17 mmol) and Hünig'sbase (42 μL, 0.24 mmol) in n-butanol (2 mL) was heated in a sealed tubeat 85° C. overnight. The reaction mixture was concentrated and purifiedby preparative HPLC. LCMS [M+H]⁺ 320.

Example 2693-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)phenol

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg,0.12 mmol), 3-(2-aminoethyl)phenol (23 mg, 0.17 mmol) and Hünig's base(42 μL, 0.24 mmol) in n-butanol (2 mL) was heated in a sealed tube at85° C. overnight. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 335.

Example 2706-(2,3-dimethylphenyl)-4-N-[3-(morpholin-4-yl)propyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg,0.12 mmol), 3-(morpholin-4-yl)propan-1-amine (24 mg, 0.17 mmol) andHünig's base (42 μL, 0.24 mmol) in n-butanol (2 mL) was heated in asealed tube at 85° C. overnight. The reaction mixture was concentratedand purified by preparative HPLC. LCMS [M+H]⁺ 342.

Example 271 tert-butylN-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-carbamate

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg,0.12 mmol), tert-butyl N-(2-aminoethyl)carbamate (27 mg, 0.17 mmol) andHünig's base (42 μL, 0.24 mmol) in n-butanol (2 mL) was heated in asealed tube at 85° C. overnight. The reaction mixture was concentratedand purified by preparative HPLC. LCMS [M+H]⁺ 358.

Example 272N-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)acetamide

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg,0.12 mmol), N-(2-aminoethyl)acetamide (17 mg, 0.17 mmol) and Hünig'sbase (42 μL, 0.24 mmol) in n-butanol (2 mL) was heated in a sealed tubeat 85° C. overnight. The reaction mixture was concentrated and purifiedby preparative HPLC. LCMS [M+H]⁺ 300.

Example 273 benzylN-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-carbamate

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg,0.12 mmol), benzyl N-(2-aminoethyl)carbamate hydrochloride (39 mg, 0.17mmol) and Hünig's base (42 μL, 0.24 mmol) in n-butanol (2 mL) was heatedin a sealed tube at 85° C. overnight. The reaction mixture wasconcentrated and purified by preparative HPLC. LCMS [M+H]⁺ 392.

Example 274 tert-butylN-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-N-methylcarbamate

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg,0.12 mmol), tert-butyl N-(2-aminoethyl)-N-methylcarbamate (29 mg, 0.17mmol) and Hünig's base (42 μL, 0.24 mmol) in n-butanol (2 mL) was heatedin a sealed tube at 85° C. overnight. The reaction mixture wasconcentrated and purified by preparative HPLC. LCMS [M+H]⁺ 372.

Example 275 tert-butylN-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-carbamate

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg,0.12 mmol), tert-butyl N-(3-aminopropyl)carbamate (29 mg, 0.17 mmol) andHünig's base (42 μL, 0.24 mmol) in n-butanol (2 mL) was heated in asealed tube at 85° C. overnight. The reaction mixture was concentratedand purified by preparative

HPLC. LCMS [M+H]⁺ 372.

Example 2766-(2,3-dimethylphenyl)-4-N-[3-(5-methyl-1H-pyrazol-3-yl)propyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg,0.12 mmol), 3-(5-methyl-1H-pyrazol-4-yl)propan-1-amine (23 mg, 0.17mmol) and Hünig's base (42 μL, 0.24 mmol) in n-butanol (2 mL) was heatedin a sealed tube at 85° C. overnight. The reaction mixture wasconcentrated and purified by preparative HPLC. LCMS [M+H]⁺ 337.

Example 2773-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-1-(morpholin-4-yl)propan-1-one

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (23 mg,0.10 mmol), 3-amino-1-(morpholin-4-yl)propan-1-one (22 mg, 0.14 mmol)and Hünig's base (35 μL, 0.20 mmol) in n-butanol (1.5 mL) was heated ina sealed tube at 85° C. overnight. The reaction mixture was concentratedand purified by preparative HPLC.

LCMS [M+H]⁺ 356.

Example 2784-N-[(4-benzylmorpholin-2-yl)methyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (23 mg,0.10 mmol), (4-benzylmorpholin-2-yl)methanamine (29 mg, 0.14 mmol) andHünig's base (35 μL, 0.20 mmol) in n-butanol (1.5 mL) was heated in asealed tube at 85° C. overnight. The reaction mixture was concentratedand purified by preparative HPLC.

LCMS [M+H]⁺ 404.

Example 2796-(2,3-dimethylphenyl)-4-N-[(4-methanesulfonylphenyl)methyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (23 mg,0.10 mmol), (4-methanesulfonylphenyl)methanamine hydrochloride (31 mg,0.14 mmol) and Hünig's base (35 μL, 0.20 mmol) in n-butanol (1.5 mL) washeated in a sealed tube at 85° C. overnight. The reaction mixture wasconcentrated and purified by preparative HPLC. LCMS [M+H]⁺ 383.

Example 2806-(2,3-dimethylphenyl)-4-N-{[4-(4-methylpiperazin-1-yl)phenyl]methyl}pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (23 mg,0.10 mmol), [4-(4-methylpiperazin-1-yl)phenyl]methanamine (29 mg, 0.14mmol) and Hünig's base (35 μL, 0.20 mmol) in n-butanol (1.5 mL) washeated in a sealed tube at 85° C. overnight. The reaction mixture wasconcentrated and purified by preparative HPLC. LCMS [M+H]⁺ 403.

Example 2814-N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (23 mg,0.10 mmol), (S)-quinuclidin-3-amine hydrochloride (29 mg, 0.14 mmol) andHünig's base (35 μL, 0.20 mmol) in n-butanol (1.5 mL) was heated in asealed tube at 85° C. overnight. The reaction mixture was concentratedand purified by preparative HPLC. LCMS [M+H]⁺ 324.

Example 282 tert-butyl2-({[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}methyl)-pyrrolidine-1-carboxylate

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (23 mg,0.10 mmol), tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (28 mg,0.14 mmol) and Hünig's base (35 μL, 0.20 mmol) in n-butanol (1.5 mL) washeated in a sealed tube at 85° C. overnight. The reaction mixture wasconcentrated and purified by preparative HPLC. LCMS [M+H]⁺ 398.

Example 283 tert-butyl4-({[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}methyl)-piperidine-1-carboxylate

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (23 mg,0.10 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (30 mg,0.14 mmol) and Hünig's base (35 μL, 0.20 mmol) in n-butanol (1.5 mL) washeated in a sealed tube at 85° C. overnight. The reaction mixture wasconcentrated and purified by preparative HPLC. LCMS [M+H]⁺ 412.

Example 2841-(3-{[2-amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (19 mg,0.070 mmol) and 1-(3-aminopropyl)pyrrolidin-2-one (49 μL, 0.35 mmol) inn-butanol (1 mL) was heated in a sealed tube at 110° C. overnight. Thereaction mixture was concentrated and purified by preparative HPLC. LCMS[M+H]⁺ 380.

Example 2851-(3-{[2-amino-6-(3-chloro-2-methylphenyl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of 4-chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (19mg, 0.076 mmol) and 1-(3-aminopropyl)pyrrolidin-2-one (53 μL, 0.38 mmol)in n-butanol (1 mL) was heated in a sealed tube at 110° C. overnight.The reaction mixture was concentrated and purified by preparative HPLC.LCMS [M+H]⁺ 360.

Example 2861-(3-{[2-amino-6-(4-fluoro-2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27mg, 0.10 mmol), (4-fluoro-2,3-dimethylphenyl)boronic acid (18 mg, 0.11mmol), potassium carbonate (28 mg, 0.20 mmol) and palladiumtetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) in1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95°C. for 2 h. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 358.

Example 2871-(3-{[2-amino-6-(4-methoxy-2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27mg, 0.10 mmol), (4-methoxy-2,3-dimethylphenyl)boronic acid (20 mg, 0.11mmol), potassium carbonate (28 mg, 0.20 mmol) and palladiumtetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) in1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95°C. for 2 h. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 370.

Example 2881-(3-{[2-amino-6-(4-methyl-1H-indazol-5-yl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27mg, 0.10 mmol), (4-methyl-1H-indazol-5-yl)boronic acid (19 mg, 0.11mmol), potassium carbonate (28 mg, 0.20 mmol) and palladiumtetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) in1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95°C. for 2 h. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 366.

Example 2891-[3-({2-amino-6-[2-methyl-5-(morpholine-4-sulfonyl)phenyl]pyrimidin-4-yl}amino)propyl]pyrrolidin-2-one

A mixture of1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27mg, 0.10 mmol), [2-methyl-5-(morpholine-4-sulfonyl)phenyl]boronic acid(31 mg, 0.11 mmol), potassium carbonate (28 mg, 0.20 mmol) and palladiumtetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) in1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95°C. for 2 h. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 475.

Example 2901-(3-{[2-amino-6-(2,3-dihydro-1-benzofuran-7-yl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27mg, 0.10 mmol), (2,3-dihydro-1-benzofuran-7-yl)boronic acid (18 mg, 0.11mmol), potassium carbonate (28 mg, 0.20 mmol) and palladiumtetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) in1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95°C. for 2 h. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 354.

Example 2911-(3-{[2-amino-6-(2,5-dimethylphenyl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27mg, 0.10 mmol), (2,5-dimethylphenyl)boronic acid (17 mg, 0.11 mmol),potassium carbonate (28 mg, 0.20 mmol) and palladiumtetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) in1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95°C. for 2 h. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 340.

Example 2921-(3-{[2-amino-6-(5-chloro-2-methylphenyl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27mg, 0.10 mmol), (5-chloro-2-methylphenyl)boronic acid (19 mg, 0.11mmol), potassium carbonate (28 mg, 0.20 mmol) and palladiumtetrakis(triphenyl-phosphine)palladium (0) (6 mg, 0.005 mmol) in1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95°C. for 2 h. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 360.

Example 2931-[3-({2-amino-6-[2-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)propyl]pyrrolidin-2-one

A mixture of1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27mg, 0.10 mmol), [2-(trifluoromethyl)phenyl]boronic acid (21 mg, 0.11mmol), potassium carbonate (28 mg, 0.20 mmol) and palladiumtetrakis-(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) in1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95°C. for 2 h. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 380.

Example 2941-(3-{[2-amino-6-(1H-indol-4-yl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27mg, 0.10 mmol), (1H-indol-4-yl)boronic acid (18 mg, 0.11 mmol),potassium carbonate (28 mg, 0.20 mmol) and palladiumtetrakis(triphenylphosphine)-palladium (0) (6 mg, 0.005 mmol) in1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95°C. for 2 h. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 351.

Example 2954-N-{[1-(4-chlorophenyl)cyclopropyl]methyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (47 mg,0.20 mmol), [1-(4-chlorophenyl)cyclopropyl]methanamine hydrochloride (65mg, 0.30 mmol) and Hünig's base (70 μL, 0.40 mmol) in n-butanol (1.5 mL)was heated in a sealed tube at 130° C. overnight. The reaction mixturewas concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 379.

Example 2964-(2-{[2-amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (41 mg,0.15 mmol), 4-(2-aminoethyl)benzene-1-sulfonamide (45 mg, 0.23 mmol) andHünig's base (39 μL, 0.23 mmol) in n-butanol (2 mL) was heated in asealed tube at 90° C. for 48 h. The reaction mixture was concentratedand purified by preparative HPLC. LCMS [M+H]⁺ 438.

Example 297 4-(2-{[2-amino-6-(3-chloro-2-methylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

A mixture of 4-chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (38mg, 0.15 mmol), 4-(2-aminoethyl)benzene-1-sulfonamide (45 mg, 0.23 mmol)and Hünig's base (39 μL, 0.23 mmol) in n-butanol (2 mL) was heated in asealed tube at 90° C. for 48 h. The reaction mixture was concentratedand purified by preparative HPLC. LCMS [M+H]⁺ 418. 1H NMR (400 MHz,DMSO-d6) δ_(H) ppm 12.33 (br. s., 1H), 8.89 (br. s., 1H), 7.77 (d, J=8.1Hz, 2H), 7.64-7.68 (m, 1H), 7.48 (d, J=8.1 Hz, 2H), 7.37-7.41 (m, 2H),7.32 (s, 2H), 6.03 (s, 1H), 3.67 (q, J=6.7 Hz, 2H), 2.98 (t, J=7.1 Hz,2H), 2.30 (s, 3H).

Example 2984-N-(Adamantan-1-yl)-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

A mixture of the 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25mg) and adamantylamine (50 mg) was heated at 150° C. for 1 h. Themixture was cooled, diluted in methanol then purified by preparativeHPLC. LCMS [M+H]⁺ 389.

Example 2996-(2,3-dichlorophenyl)-4-N-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg)and (1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine (50 mg)was heated at 150° C. for 1 h. The mixture was cooled, diluted inmethanol then purified by preparative HPLC. LCMS [M+H]⁺ 391.

Example 3006-(2,3-Dichlorophenyl)-4-N-({3-[(4-methylpiperidin-1-yl)methyl]phenyl}methyl)-pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg)and {3-[(4-methylpiperidin-1-yl)methyl]phenyl}methanamine (50 mg) washeated at 150° C. for 1 h. The mixture was cooled, diluted in methanoland then purified by preparative HPLC. LCMS [M+H]⁺ 456.

Example 3014-(2-{[2-Amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}ethyl)phenol

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg)and 4-(2-aminoethyl)phenol (50 mg) was heated at 150° C. for 1 h. Themixture was cooled, diluted in methanol then purified by preparativeHPLC. LCMS [M+H]⁺ 375.

Example 302 Ethyl4-{[2-amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}piperidine-1-carboxylate

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg)and ethyl 4-aminopiperidine-1-carboxylate (50 mg) was heated at 150° C.for 1 h. The mixture was cooled, diluted in methanol then purified bypreparative HPLC. LCMS [M+H]⁺ 410.

Example 303N-(4-{[2-Amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}butyl)acetamide

A solution of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg;0.1 mmol) in n-BuOH (1.0 ml) was heated at 130° C. withN-(4-aminobutyl)acetamide (1 eq.) and triethylamine (1 eq). After 18 hthe reaction was halted and evaporated. The residue was purified bypreparative HPLC. LCMS [M+H]⁺ 368.

Example 3046-(2,3-Dichlorophenyl)-4-N-{tricyclo[3.3.1.0^(3,7)]nonan-3-yl}pyrimidine-2,4-diamine

A solution of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg;0.1 mmol) in n-BuOH (1.0 ml) was heated at 130° C. withtricyclo[3.3.1.0^(3,7)]nonan-3-amine (1 eq) and triethylamine (1 eq).After 18 h the reaction was halted and evaporated. The residue waspurified by preparative HPLC. LCMS [M+H]⁺ 375.

Example 3056-(2,3-Dichlorophenyl)-4-N-{[4-(1,2,3-thiadiazol-4-yl)phenyl]methyl}pyrimidine-2,4-diamine

A solution of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg;0.1 mmol) in n-BuOH (1.0 ml) was heated at 130° C. with[4-(1,2,3-thiadiazol-4-yl)phenyl]methanamine (1 eq) and triethylamine (1eq). After 18 h the reaction was halted and evaporated. The residue waspurified by preparative HPLC. LCMS [M+H]⁺ 429.

Example 3064-N-[2-(1-Benzylpiperidin-4-yl)ethyl]-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

A solution of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg;0.1 mmol) in n-BuOH (1.0 ml) was heated at 130° C. with2-(1-benzylpiperidin-4-yl)ethan-1-amine (1 eq) and triethylamine (1 eq).After 18 h the reaction was halted and evaporated. The residue waspurified by preparative HPLC. LCMS [M+H]⁺ 456.

Example 3076-(2,3-Dichlorophenyl)-4-N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)pyrimidine-2,4-diamine

A solution of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg;0.1 mmol) in n-BuOH (1.0 ml) was heated at 130 degrees with2,3-dihydro-1,4-benzodioxin-2-ylmethanamine (1 eq) and triethylamine (1eq). After 18 h the reaction was halted and evaporated. The residue waspurified by preparative HPLC. LCMS [M+H]⁺ 403.

Example 308N-{3-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}-3-hydroxypyridine-2-carboxamide

Equimolar quantities of 3-hydroxypyridine-2-carboxylic acid (0.24 mmol)and 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine were dissolvedin 2 ml DMF followed by addition of hydroxybenzotriazole (1.0 eq) andN,N′-dicyclohexylcarbodiimide (1.5 eq). The solution was stirred at rtovernight. The mixture was then filtrated and purified by preparativeHPLC.

LCMS [M+H]⁺ 337; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 12.15 (1H, br. s.),11.17 (1H, s), 8.86 (1H, m, J=5.05 Hz), 8.25-8.35 (2H, m), 8.03 (1H, dd,J=8.08, 1.26 Hz), 7.59-7.68 (2H, m), 7.52 (2H, dd, J=8.46, 1.39 Hz),6.36 (1H, s), 2.95 (3H, d, J=4.80 Hz).

Example 309N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}prop-2-enamide

To a stirred suspension of6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.29 mmol) andtriethylamine (1.5 eq.) in acetonitrile (2 mL) at 0° C. was slowly addedprop-2-enoyl chloride (1.0 eq.). The mixture was allowed to warm to rtand stirred for 3 h. The mixture was concentrated and purified bypreparative HPLC.

LCMS [M+H]⁺ 270; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 10.35 (1H, s), 8.23(1H, t, J=1.89 Hz), 7.79 (1H, d, J=8.08 Hz), 7.56-7.69 (4H, m),7.34-7.52 (4H, m), 6.88 (1H, s), 6.84 (1H, s), 6.18 (1H, s), 5.98 (2H,s), 2.80 (3H, d, J=4.80 Hz).

Example 310(2E)-N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-3-phenylprop-2-enamide

To a suspension of the6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.25 mmol) andtriethylamine (1.5 eq.) in acetonitrile (2 mL) at 0° C. was added dropwise, with stirring, the (E)-3-phenylprop-2-enoyl chloride (1.0 eq.).The mixture was allowed to warm to rt, and stirred for 3 h. The mixturewas concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 346; ¹HNMR (400 MHz, DMSO-d₆) δ_(H) ppm 10.35 (s, 1H), 8.23 (t, J=1.89 Hz, 1H),7.79 (d, J=8.08 Hz, 1H), 7.56-7.69 (m, 4H), 7.34-7.52 (m, 4H), 6.88 (s,1H), 6.84 (s, 1H), 6.18 (s, 1H), 5.98 (s, 2H), 2.80 (d, J=4.80 Hz, 3H).

Example 311N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]-2-methylphenyl}prop-2-enamide

To a suspension of6-(3-amino-2-methyl-phenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.39mmol) and triethylamine (1.5 eq.) in acetonitrile (3 ml) at 0° C. wasadded drop wise, with stirring, prop-2-enoyl chloride (1.0 eq.). Themixture was allowed to warm to rt, and stirred for 3 h. The mixture wasconcentrated and purified by preparative HPLC. LCMS [M+H]⁺ 284; ¹H NMR(400 MHz, DMSO-d₆) δ_(H) ppm 9.57 (1H, s), 7.41 (1H, d, J=7.58 Hz), 7.20(1H, t, J=7.83 Hz), 7.10 (1H, d, J=6.82 Hz), 6.83 (1H, br. s.), 6.54(1H, dd, J=17.05, 10.23 Hz), 6.25 (1H, dd, J=17.05, 2.15 Hz), 5.97 (2H,s), 5.73-5.78 (1H, m), 5.71 (1H, s), 2.77 (3H, d, J=4.55 Hz), 2.14 (3H,s).

Example 312(2E)-N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-4-(dimethylamino)but-2-enamide

To a solution of 6-(3-aminophenyl)-4-N-methylpyrimidine-2,4-diamine(0.29 mol) in acetonitrile (4 mL) was added successively(E)-4-(dimethylamino)but-2-enoic acid; hydrochloride (1.0 eq.),triethylamine (3.0 eq.) and n-propanephosphonic acid anhydride (T3P, 2.0eq.). The resulting mixture was stirred at rt overnight. The solutionwas then filtrated and purified by preparative HPLC. LCMS [M+H]⁺ 327; ¹HNMR (400 MHz, DMSO-d₆) δ_(H) ppm 10.17 (1H, s), 8.20 (1H, t, J=1.77 Hz),7.71 (1H, d, J=8.08 Hz), 7.58 (1H, d, J=7.83 Hz), 7.36 (1H, t, J=7.83Hz), 6.81-6.96 (1H, m), 6.70-6.80 (1H, m), 6.28 (1H, dt, J=15.35, 1.55Hz), 6.16 (1H, s), 5.97 (2H, s), 3.06 (2H, dd, J=6.06, 1.52 Hz), 2.79(3H, d, J=4.80 Hz), 2.18 (6H, s).

Example 313N-{3-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}ethene-1-sulfonamide

To a suspension of 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine(0.20 mmol) and triethylamine (1.1 eq.) in acetonitrile (1.5 mL) at −60°C. was added drop wise, with stirring, ethenesulfonyl chloride (0.9 eq.)in 0.5 ml acetonitrile. The mixture was allowed to warm to rt, andstirred for 2 h. The solution was then filtrated and purified bypreparative HPLC. LCMS [M+H]⁺ 306; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm11.98 (1H, br. s.), 10.38 (1H, br. s.), 8.79 (1H, br. s.), 7.31-7.60(4H, m), 6.85 (1H, dd, J=16.42, 9.85 Hz), 6.25 (1H, s), 6.18 (1H, d,J=16.42 Hz), 6.08 (1H, d, J=9.85 Hz), 2.93 (3H, d, J=4.80 Hz).

Example 314N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}prop-2-ynamide

To a solution of 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine(0.30 mol) in acetonitrile (5 mL) at 0° C. was added successivelyprop-2-ynoic acid (1.0 eq.), triethylamine (2.0 eq.) andn-propanephosphonic acid anhydride (T3P, 1.7 eq.). The resulting mixturewas stirred at rt overnight. The solution was then filtrated andpurified by preparative HPLC. LCMS [M+H]⁺ 268; ¹H NMR (400 MHz, DMSO-d₆)δ_(H) ppm 8.19 (1H, br. s.), 7.84 (1H, d, J=7.83 Hz), 7.65 (1H, d,J=7.83 Hz), 7.46 (1H, d, J=13.39 Hz), 7.38 (1H, t, J=7.83 Hz), 7.00 (1H,d, J=13.89 Hz), 6.28 (1H, br. s.), 5.97 (2H, s), 2.78 (3H, d, J=4.55Hz).

Example 315 N-{3-[2-Amino-6-(methylamino)pyri midin-4-yl]phenyl}-2-oxopropanamide

To a solution of 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine(0.39 mol) in acetonitrile (4 mL) was added successively pyruvic acid(1.0 eq.), triethylamine (2.5 eq.) and n-propanephosphonic acidanhydride (T3P, 2.0 eq.). The resulting mixture was stirred at rtovernight. The solution was then filtrated and purified by preparativeHPLC. LCMS [M+H]⁺ 286.

Example 316N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-2-oxo-2-phenylacetamide

To a solution of 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine(0.42 mol) in acetonitrile (4 mL) was added successively2-oxo-2-phenyl-acetic acid (0.9 eq.), triethylamine (2.5 eq.) andn-propanephosphonic acid anhydride (T3P, 2.0 eq.). The resulting mixturewas stirred at rt overnight. The mixture was concentrated and purifiedby preparative HPLC. LCMS [M+H]⁺ 348; ¹H NMR (400 MHz, DMSO-d₆) δ_(H)ppm 8.30-8.36 (1H, m), 8.00-8.11 (2H, m), 7.66-7.84 (3H, m), 7.59-7.66(2H, m), 7.45 (1H, t, J=7.96 Hz), 6.90 (1H, br. s.), 6.19 (1H, s), 6.01(2H, s), 2.80 (3H, d, J=4.80 Hz).

Example 317N-{4-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}prop-2-enamide

To a suspension of 6-(4-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine(0.29 mmol) and triethylamine (1.5 eq.) in tetrahydrofuran (2 ml) at 0°C. was added drop wise, with stirring, prop-2-enoyl chloride (1.0 eq.).The mixture was allowed to warm to rt, and stirred for 3 h. The mixturewas concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 270; ¹HNMR (400 MHz, DMSO-d6) δ_(H) ppm 10.28 (1H, s), 7.89 (2H, d, J=8.8 Hz),7.58-7.75 (2H, m), 6.76 (1H, br. s.), 6.40-6.49 (1H, m), 6.24-6.30 (1H,m), 6.17 (1H, s), 5.94 (2H, s), 5.58-5.80 (1H, m), 2.79 (3H, d, J=4.8Hz).

Example 318N-({4-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}methyl)prop-2-enamide

To a suspension of6-[4-(aminomethyl)phenyl]-4-N-methyl-pyrimidine-2,4-diamine (0.29 mmol)and triethylamine (1.5 eq.) in tetrahydrofuran (2 ml) at 0° C. was addeddrop wise, with stirring, prop-2-enoyl chloride (1.0 eq.). The mixturewas allowed to warm to rt and stirred for 3 h. The mixture wasconcentrated and purified by preparative HPLC. LCMS [M+H]⁺ 284.

Example 319N-({3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}methyl)prop-2-enamide

To a suspension of6-[3-(aminomethyl)phenyl]-4-N-methyl-pyrimidine-2,4-diamine (0.16 mmol)and triethylamine (1.5 eq.) acetonitrile (4 mL) at 0° C. was added dropwise, with stirring, prop-2-enoyl chloride (1.0 eq.). The mixture wasallowed to warm to room temperature, and stirred for 3 h. The mixturewas concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 284.

Example 320N-{3-[2-Amino-6-(ethylamino)pyrimidin-4-yl]-4-methylphenyl}prop-2-enamide

To a suspension of6-(5-amino-2-methyl-phenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.48mmol) and triethylamine (1.7 eq.) in acetonitrile (3 mL) at 0° C. wasadded drop wise, with stirring, prop-2-enoyl chloride (1.0 eq.). Themixture was allowed to warm to rt and stirred for 3 h. The mixture wasconcentrated and purified by preparative HPLC. LCMS [M+H]⁺ 284; ¹H NMR(400 MHz, DMSO-d₆) δ_(H) ppm 10.10 (1H, s), 7.46-7.75 (2H, m), 7.16 (1H,d, J=8.34 Hz), 6.80 (1H, br. s.), 6.37-6.46 (1H, m), 6.23 (1H, dd,J=17.05, 2.15 Hz), 5.95 (2H, s), 5.62-5.84 (2H, m), 2.77 (3H, d, J=4.55Hz), 2.27 (3H, s).

Example 321N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-5-chloro-2-hydroxybenzamide

Equimolar quantities of 5-chloro-2-hydroxy-benzoic acid and6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.24 mmol) weredissolved in DMF (2 mL) followed by adding hydroxybenzotriazole (1.0 eq)and N,N′-dicyclohexylcarbodiimide (1.5 eq). The solution was stirredunder rt overnight. The mixture was then filtrated and purified bypreparative HPLC. LCMS [M+H]⁺ 370; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm15.10 (1H, br. s), 8.08-8.16 (1H, m), 7.86 (1H, d, J=7.58 Hz), 7.64 (1H,d, J=3.03 Hz), 7.49 (1H, d, J=7.33 Hz), 7.32 (1H, t, J=7.96 Hz), 6.93(1H, dd, J=8.84, 3.03 Hz), 6.78-6.89 (1H, m), 6.40 (1H, d, J=8.84 Hz),6.20 (1H, s), 6.03 (2H, s), 2.80 (3H, d, J=4.55 Hz).

Example 322N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-2-hydroxyacetamide

Equimolar quantities of 2-hydroxyacetic acid and6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.24 mmol) weredissolved in 2 ml DMF followed by adding hydroxybenzotriazole (1.0 eq)in 1 mL DMF and N,N′-dicyclohexylcarbodiimide (1.5 eq, dissolved inxylene). The solution was stirred under room temperature overnight. Themixture was then filtrated and purified by preparative. LCMS [M+H]⁺ 274;¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 12.06 (1H, br. s.), 9.75-10.10 (1H,m), 8.83 (1H, d, J=4.55 Hz), 8.22 (1H, s), 7.84 (1H, d, J=9.35 Hz), 7.54(1H, t, J=7.96 Hz), 7.40 (1H, d, J=8.08 Hz), 6.30 (1H, s), 5.61-5.97(1H, m), 4.03 (2H, s), 2.94 (3H, d, J=4.80 Hz).

Example 323N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-2-(4-chlorophenyl)-2-hydroxyacetamide

Equimolar quantities of6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.24 mmol) and2-(4-chlorophenyl)-2-hydroxy-acetic acid were dissolved in 2 ml DMFfollowed by adding hydroxybenzotriazole (1.0 eq) in 1 mL DMF andN,N′-dicyclohexylcarbodiimide (1.5 eq.; as a solution in xylene). Thesolution was stirred at rt overnight. The mixture was then filtrated andpurified by preparative HPLC. LCMS [M+H]⁺ 384; ¹H NMR (400 MHz, DMSO-d₆)δ_(H) ppm 10.05 (1H, s), 8.22 (1H, t, J=1.89 Hz), 7.69 (1H, d, J=8.59Hz), 7.59 (1H, d, J=6.57 Hz), 7.52-7.57 (2H, m), 7.40-7.45 (2H, m), 7.34(1H, t, J=7.96 Hz), 6.85 (1H, br. s.), 6.14 (1H, s), 6.04 (2H, br. s.),5.97 (1H, s), 5.14 (1H, s), 2.78 (3H, d, J=4.80 Hz).

Example 324N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-2-hydroxy-2-phenylacetamide

Equimolar quantities of 2-hydroxy-2-phenyl-acetic acid and6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.24 mmol) weredissolved in DMF (2 mL) followed by adding hydroxybenzotriazole (1.0 eq)in DMF (1 mL) and N,N′-dicyclohexylcarbodiimide (1.5 eq, dissolved inxylene). The solution was stirred under rt overnight. The mixture wasthen filtrated and purified by preparative HPLC. LCMS [M+H]⁺ 350; ¹H NMR(400 MHz, DMSO-d₆) δ_(H) ppm 11.86 (1H, br. s.), 10.25 (2H, s), 8.25(1H, s), 7.85 (1H, d, J=8.59 Hz), 7.48-7.63 (3H, m), 7.26-7.46 (4H, m),6.56 (1H, d, J=4.29 Hz), 6.28 (1H, s), 5.15 (1H, d, J=3.79 Hz), 2.93(3H, d, J=4.80 Hz).

Example 325N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-4-oxo-4-(pyrrolidin-1-yl)butanamide

Equimolar quantities of 4-oxo-4-pyrrolidin-1-yl-butanoic acid and6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.24 mmol) weredissolved in DMF (2 mL) followed by adding hydroxybenzotriazole (1.0 eq)in DMF (1 mL) and N,N′-dicyclohexylcarbodiimide (1.5 eq, dissolved inxylene). The solution was stirred at rt overnight. The mixture was thenfiltrated and purified by preparative HPLC.

LCMS [M+H]⁺ 369.

Example 326N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-2-hydroxybenzamide

Equimolar quantities of 2-hydroxybenzoic acid and6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.24 mmol) weredissolved in MeCN (2 mL) followed by addingN,N′-dicyclohexylcarbodiimide (1.25 eq). The solution was stirred at rtovernight. The mixture was then filtrated and purified by preparativeHPLC. LCMS [M+H]⁺ 336.

Example 3271-{4-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-2,2,2-trifluoroethan-1-one

Tetrakis(triphenylphosphine)palladium (0) (5 mol %) was added to astirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (0.25mmol), [4-(trifluoroacetyl)phenyl]boronic ester (1.3 eq.), sodiumcarbonate (3.2 eq.), dioxane (2 mL) and water (0.5 mL) in a tube. Thetube was sealed and the reaction was heated at 90° C. for 5 hours. Themixture was then filtrated and purified by preparative HPLC. LCMS [M+H]⁺297.

Example 328 6-[3-(Aminomethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Tetrakis(triphenylphosphine)palladium (0) (5 mol %) was added to astirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (2.00mmol), [3-(aminomethyl)phenyl]boronic acid (1.3 eq.), sodium carbonate(3.2 eq.), dioxane (4 mL) and water (1 mL) in a tube. The tube wassealed and the reaction was heated at 90° C. overnight. The solvent wereremoved in vacuum and to the remaining solid was added ethyl acetate andwashed with water. The organic phase was dried over magnesium sulfate.The crude material was then purified by flash chromatography (0>15%MeOH/DCM) to give the title compound. LCMS [M+H]⁺ 230; ¹H NMR (400 MHz,DMSO-d₆) δ_(H) ppm 7.90 (1H, s), 7.75 (1H, d, J=6.32 Hz), 7.35-7.42 (3H,m), 6.82 (1H, br. S), 6.21 (1H, s), 5.98 (2H, s), 3.79 (2H, s), 2.79(3H, d, J=4.80 Hz).

Example 329 6-[4-(Aminomethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Tetrakis(triphenylphosphine)palladium (0) (5 mol %) was added to astirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (1.00mmol), [4-(aminomethyl)phenyl]boronic acid (1.3 eq.), sodium carbonate(4.2 eq.), dioxane (4 ml) and water (1 ml) in a tube. The tube wassealed and the reaction was heated at 90° C. overnight. The solvent wereremoved in vacuum and to the remaining solid was added ethyl acetate andwashed with water. The organic phase was dried over magnesium sulfate.The crude material was then purified by flash chromatography (0→15%MeOH/DCM) to give the title compound. LCMS [M+H]⁺ 230; ¹H NMR (400 MHz,DMSO-d₆) δ_(H) ppm 7.86 (2H, d, J=7.58 Hz), 7.38 (2H, d, J=8.59 Hz),6.19 (1H, s), 5.96 (2H, s), 3.76 (2H, s), 2.79 (3H, d, J=4.80 Hz).

Example 3304-(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.12mmol), 4-(2-aminoethyl)benzene-1-sulfonamide (0.9 eq.) and triethylamine(1.5 eq.) in acetonitrile/ethanol/methanol 5:3:2 (1 mL) was heated in asealed tube at 95° C. overnight. Methanol was added, and the mixture wasfiltered and purified by preparative HPLC. LCMS [M+H]⁺ 398; ¹H NMR (400MHz, DMSO-d₆) δ_(H) ppm 12.28 (1H, br. s.), 8.87 (1H, br. s.), 7.77 (2H,d, J=8.34 Hz), 7.48 (2H, d, J=8.34 Hz), 7.37 (1H, d, J=7.33 Hz), 7.32(2H, s), 7.23-7.28 (1H, m), 7.18-7.23 (1H, m), 5.99 (1H, s), 3.67 (2H,q, J=6.82 Hz), 2.98 (2H, t, J=7.20 Hz), 2.31 (3H, s), 2.17 (3H, s).

Example 3316-(2,3-Dimethylphenyl)-4-N-[2-(4-methanesulfonylphenyl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.15mmol), 2-(4-methanesulfonylphenyl)ethan-1-amine (1.2 eq.) andN,N-diisopropylethylamine (2.25 eq.) in n-butanol (0.3 mL) was heated ina sealed tube at 110° C. overnight.

Methanol was added and the mixture was filtered and purified bypreparative HPLC. LCMS [M+H]⁺ 397.

Example 3326-(2,3-Dimethylphenyl)-4-N-[2-(5-methyl-1H-1,2,4-triazol-3-yl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.15mmol), 2-(5-methyl-1H-1,2,4-triazol-3-yl)ethan-1-amine (0.9 eq.) andtriethylamine (1.5 eq.) in acetonitrile/ethanol/methanol 5:3:2 (1 mL)was heated in a sealed tube at 95° C. overnight. Methanol was added, andthe mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺324.

Example 3334-(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)benzonitrile

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.15mmol), 4-(2-aminoethyl)benzonitrile (1.2 eq.) andN,N-diisopropylethylamine (2.25 eq.) in n-butanol (0.3 mL) was heated ina sealed tube at 110° C. overnight. Methanol was added, and the mixturewas filtered and purified by preparative HPLC. LCMS [M+H]⁺ 344; ¹H NMR(400 MHz, DMSO-d₆) δ_(H) ppm 12.36 (1H, br. s.), 8.87 (1H, t, J=5.31Hz), 7.80 (2H, d, J=8.08 Hz), 7.51 (2H, d, J=8.34 Hz), 7.37 (1H, d,J=7.33 Hz), 7.23-7.28 (1H, m), 7.16-7.22 (1H, m), 5.98 (1H, s), 3.67(2H, q, J=6.65 Hz), 2.99 (2H, t, J=7.20 Hz), 2.31 (3H, s), 2.17 (3H, s).

Example 3346-(2,3-Dimethylphenyl)-4-N-[2-(pyridin-4-yl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.15mmol), 2-(pyridin-4-yl)ethan-1-amine (1.2 eq.) andN,N-diisopropylethylamine (1.25 eq.) in n-butanol (0.3 ml) was heated ina sealed tube at 110° C. overnight. Methanol was added, and the mixturewas filtered and purified by preparative HPLC. LCMS [M+H]⁺ 320; ¹H NMR(400 MHz, DMSO-d₆) δ_(H) ppm 12.45 (1H, br. s.), 8.93 (1H, t, J=5.56Hz), 8.76 (2H, d, J=6.32 Hz), 7.80 (2H, d, J=6.32 Hz), 7.37 (1H, d,J=7.33 Hz), 7.25 (1H, t, J=7.58 Hz), 7.17-7.21 (1H, m), 5.99 (1H, s),3.68-3.83 (2H, m), 3.13 (2H, t, J=7.07 Hz), 2.31 (3H, s), 2.17 (3H, s).

Example 3354-(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethoxy)benzonitrile

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.15mmol), 4-(2-aminoethoxy)benzonitrile (1.2 eq.) andN,N-diisopropylethylamine (1.25 eq.) in n-butanol (0.3 mL) was heated ina sealed tube at 110° C. overnight. Methanol was added, and the mixturewas filtered and purified by preparative HPLC. LCMS [M+H]⁺ 360; ¹H NMR(400 MHz, DMSO-d₆) δ_(H) ppm 12.37 (1H, br. s.), 9.02 (1H, t, J=5.31Hz), 7.77-7.83 (2H, m), 7.37 (1H, d, J=7.33 Hz), 7.23-7.29 (1H, m),7.18-7.22 (1H, m), 7.12-7.18 (2H, m), 6.06 (1H, s), 4.29 (2H, t, J=5.43Hz), 3.82 (2H, q, J=5.22 Hz), 2.31 (3H, s), 2.17 (3H, s).

Example 3364-({[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}methyl)benzene-1-sulfonamide

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.08mmol), 4-(aminomethyl)benzene-1-sulfonamide (0.9 eq.) and triethylamine(1.5 eq.) in acetonitrile/ethanol/methanol 5:3:2 (1 mL) was heated in asealed tube at 95° C. overnight. Methanol was added, and the mixture wasfiltered and purified by preparative HPLC. LCMS [M+H]⁺ 384; ¹H NMR (400MHz, DMSO-d₆) δ_(H) ppm 7.74-7.81 (2H, m), 7.49-7.54 (2H, m), 7.46 (1H,t, J=5.68 Hz), 7.30 (2H, s), 7.12-7.21 (1H, m), 7.01-7.12 (2H, m), 6.00(2H, s), 5.76 (1H, br. s.), 4.57 (2H, br. s.), 2.26 (3H, s), 2.15 (3H,s).

Example 3371-(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-1,2-dihydropyridin-2-one

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.11mmol), 1-(2-aminoethyl)-1,2-dihydropyridin-2-one (0.9 eq.) andtriethylamine (1.5 eq.) in acetonitrile/ethanol/methanol 5:3:2 (1 mL)was heated in a sealed tube at 95° C. overnight. Methanol was added, andthe mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺336.

Example 3383-({[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}methyl)-1,2-dihydropyridin-2-one

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.11mmol), 3-(aminomethyl)-1,2-dihydropyridin-2-one (0.9 eq.) andtriethylamine (1.5 eq.) in acetonitrile/ethanol/methanol 5:3:2 (1 ml)was heated in a sealed tube at 95° C. overnight. Methanol was added, andthe mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺322.

Example 3396-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-5H,6H,7H-pyrrolo[3,4-b]pyridin-5-one

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.12mmol), 6-(3-aminopropyl)-5H,6H,7H-pyrrolo[3,4-b]pyridin-5-one (0.9 eq.)and triethylamine (1.5 eq.) in acetonitrile/ethanol/methanol 5:3:2 (1mL) was heated in a sealed tube at 95° C. overnight. Methanol was added,and the mixture was filtered and purified by preparative HPLC. LCMS[M+H]⁺ 389.

Example 3406-({[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}methyl)pyridin-3-ol

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.08mmol), 6-(aminomethyl)pyridin-3-ol hydrochloride (0.9 eq.) andtriethylamine (2.5 eq.) in acetonitrile/ethanol/methanol 5:3:2 (1 mL)was heated in a sealed tube at 95° C. overnight. Methanol was added, andthe mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺322.

Example 3414-N-[2-(3-Chlorophenyl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from2-(3-chlorophenyl)ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 353; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 2.24 (s, 3H) 2.31 (s, 3H) 2.88 (t, J=7.07Hz, 2H) 3.56 (d, J=5.81 Hz, 2H) 4.86-5.12 (m, 3H) 5.79 (s, 1H) 7.07-7.15(m, 3H) 7.17 (q, J=4.04 Hz, 1H) 7.20-7.26 (m, 3H).

Example 3426-(2,3-Dimethylphenyl)-4-N-[3-(1H-imidazol-1-yl)propyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from3-(1H-imidazol-1-yl)propan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 323; ¹HNMR (400 MHz, CD₃OD) δ_(H) ppm 2.11 (t, J=6.82 Hz, 2H) 2.20 (s, 3H) 2.32(s, 3H) 3.38 (br. s., 2H) 4.13 (t, J=6.95 Hz, 2H) 5.82 (s, 1H) 6.98 (br.s., 1H) 7.05-7.23 (m, 4H) 7.69 (br. s., 1H).

Example 3434-N-[2-(4-Chlorophenyl)propyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from2-(4-chlorophenyl)propan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 367; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 1.31 (d, J=7.07 Hz, 3H) 2.23 (s, 3H) 2.31(s, 3H) 2.97-3.09 (m, 1H) 3.28-3.40 (m, 1H) 3.46-3.66 (m, 1H) 4.74 (br.s., 1H) 4.95 (br. s., 2H) 5.74 (s, 1H) 7.09-7.14 (m, 2H) 7.14-7.19 (m,3H) 7.28-7.33 (m, 2H).

Example 3446-(2,3-Dimethylphenyl)-4-N-[2-(4-fluorophenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from2-(4-fluorophenyl)ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 337; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 2.23 (s, 3H) 2.29-2.34 (m, 3H) 2.89-2.96(m, 3H) 3.49-3.60 (m, 1H) 3.76 (d, J=6.06 Hz, 3H) 5.77 (s, 4H) 7.00-7.07(m, 3H) 7.08-7.12 (m, 2H) 7.13-7.22 (m, 5H) 7.28-7.32 (m, 1H).

Example 3456-(2,3-Dimethylphenyl)-4-N-[2-(4-methoxyphenyl)-2-(pyrrolidin-1-yl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from2-(4-methoxyphenyl)-2-(pyrrolidin-1-yl)ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 418; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 1.74-1.81 (m, 4H) 2.22 (s, 3H) 2.30 (s,3H) 2.46-2.69 (m, 5H) 3.49 (br. s., 2H) 3.81 (s, 3H) 4.88 (br. s., 2H)5.04-5.18 (m, 1H) 5.74 (s, 1H) 6.85-6.90 (m, 2H) 7.09-7.12 (m, 2H)7.13-7.17 (m, 1H) 7.24-7.29 (m, 2H).

Example 3464-N-{[4-(Dimethylamino)phenyl]methyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from4-(aminomethyl)-N,N-dimethylaniline and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 348.

Example 3474-N-[2-(Benzenesulfonyl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from2-(benzenesulfonyl)ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 383; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 2.22 (s, 3H) 2.31 (s, 3H) 3.41-3.46 (m,2H) 3.86 (q, J=6.06 Hz, 2H) 5.10 (br. s., 2H) 5.41-5.53 (m, 1H) 5.76 (s,1H) 7.07-7.16 (m, 2H) 7.16-7.20 (m, 1H) 7.57-7.63 (m, 2H) 7.66-7.71 (m,1H) 7.92-7.97 (m, 2H),

Example 3486-(2,3-Dimethylphenyl)-4-N-{[1-(4-fluorophenyl)-1H-pyrazol-4-yl]methyl}pyrimidine-2,4-diamine

Prepared according to general procedure 9 from[1-(4-fluorophenyl)-1H-pyrazol-4-yl]methanamine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 389; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 2.22 (s, 3H) 2.29 (s, 3H) 4.47 (d, J=5.31Hz, 2H) 5.11-5.41 (m, 3H) 5.85 (s, 1H) 7.10-7.19 (m, 5H) 7.59-7.65 (m,2H) 7.68 (s, 1H) 7.85 (s, 1H)

Example 3496-(2,3-dimethylphenyl)-4-N-{2-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]ethyl}pyrimidine-2,4-diamine

Prepared according to general procedure 9 from2-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 387.

Example 3506-(2,3-Dimethylphenyl)-4-N-{[1-(pyrimidin-2-yl)piperidin-3-yl]methyl}pyrimidine-2,4-diamine

Prepared according to general procedure 9 from[1-(pyrimidin-2-yl)piperidin-3-yl]methanamine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 390; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 1.41 (m, 1H) 1.48-1.60 (m, 1H) 1.75 (m,1H) 1.85-1.98 (m, 2H) 2.24 (s, 3H) 2.31 (s, 3H) 3.13-3.48 (m, 4H)4.15-4.24 (m, 1H) 4.30 (m, 1H) 5.11 (br. s., 2H) 5.39 (br. s., 1H) 5.82(s, 1H) 6.45 (t, J=4.80 Hz, 1H) 7.10-7.19 (m, 3H) 8.28-8.31 (d, J=4.80Hz, 2H).

Example 3516-(2,3-Dimethylphenyl)-4-N-[2-(6-methoxy-1H-1,3-benzodiazol-2-yl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from2-(6-methoxy-1H-1,3-benzodiazol-2-yl)ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 389; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 2.16 (s, 3H) 2.24 (s, 3H) 3.12 (t, J=6.19Hz, 2H) 3.81 (s, 3H) 3.82-3.90 (m, 2H) 5.11-5.43 (m, 2H) 5.79 (s, 1H)5.88 (br. s., 1H) 6.85 (dd, J=8.72, 2.40 Hz, 1H) 7.01 (d, J=8.08 Hz, 2H)7.05 (t, J=7.58 Hz, 1H) 7.12 (d, J=6.82 Hz, 1H) 7.40 (d, J=8.59 Hz, 1H).

Example 3526-(2,3-Dimethylphenyl)-4-N-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from2-(4-methyl-1,3-thiazol-5-yl)ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 340; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 2.23 (s, 3H) 2.30 (s, 3H) 2.40 (s, 3H)3.07 (t, J=6.82 Hz, 2H) 3.56 (q, J=6.48 Hz, 2H) 5.01 (br. s., 3H) 5.79(s, 1H) 7.11-7.14 (m, 2H) 7.17 (q, J=4.55 Hz, 1H) 8.59 (s, 1H).

Example 3534-N-[(3-Cyclopropyl-1H-pyrazol-5-yl)methyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from(3-cyclopropyl-1H-pyrazol-5-yl)methanamine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 335; ¹HNMR (400 MHz, CD₃OD) δ_(H) ppm 0.63-0.71 (m, 2H) 0.93 (br. d, J=7.33 Hz,2H) 1.83-1.93 (m, 1H) 2.18 (s, 3H) 2.31 (s, 3H) 4.50 (br. s., 2H) 5.86(s, 1H) 5.92 (s, 1H) 7.03-7.22 (m, 3H).

Example 3544-N-[3-(3,5-Dimethyl-1H-pyrazol-1-yl)propyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from3-(3,5-dimethyl-1H-pyrazol-1-yl)propan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 351; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 2.05 (quin, J=6.44 Hz, 2H) 2.20 (s, 3H)2.21 (d, J=0.51 Hz, 3H) 2.23 (s, 3H) 2.31 (s, 3H) 3.28-3.38 (m, 2H) 4.07(t, J=6.57 Hz, 2H) 5.00 (br. s., 2H) 5.36 (br. s., 1H) 5.74 (s, 1H) 5.78(s, 1H) 7.10-7.14 (m, 2H) 7.16 (q, J=4.29 Hz, 1H).

Example 3556-(2,3-Dimethylphenyl)-4-N-{[1-(pyridin-2-yl)piperidin-3-yl]methyl}pyrimidine-2,4-diamine

Prepared according to general procedure 9 from[1-(pyridin-2-yl)piperidin-3-yl]methanamine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 389; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 1.28-1.40 (m, 1H) 1.53-1.67 (m, 1H)1.73-1.83 (m, 1H) 1.88-2.00 (m, 2H) 2.24 (s, 3H) 2.31 (s, 3H) 3.00 (br.t, J=11.40 Hz, 1H) 3.09 (ddd, J=12.95, 10.04, 3.28 Hz, 1H) 3.17-3.40 (m,2H) 3.91 (dt, J=12.88, 4.29 Hz, 1H) 4.10 (dd, J=12.88, 3.03 Hz, 1H) 4.99(br. s., 2H) 5.31 (d, J=2.02 Hz, 1H) 5.83 (s, 1H) 6.57 (ddd, J=7.07,4.93, 0.88 Hz, 1H) 6.62-6.67 (m, 1H) 7.12-7.19 (m, 3H) 7.45 (ddd,J=8.91, 7.01, 2.02 Hz, 1H) 8.16 (ddd, J=4.93, 2.02, 0.88 Hz, 1H).

Example 3566-(2,3-Dimethylphenyl)-4-N-[(2-phenyl-2H-1,2,3-triazol-4-yl)methyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from(2-phenyl-2H-1,2,3-triazol-4-yl)methanamine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 372; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 2.21 (s, 3H) 2.28 (s, 3H) 4.67 (br d,J=5.31 Hz, 2H) 5.17 (br. s., 2H) 5.58-5.70 (m, 1H) 5.87 (s, 1H)7.08-7.18 (m, 3H) 7.32-7.38 (m, 1H) 7.45-7.51 (m, 2H) 7.74 (s, 1H)8.01-8.06 (m, 2H).

Example 357N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-4-chlorobenzene-1-sulfonamide

Prepared according to general procedure 10 from4-chlorobenzene-1-sulfonyl chloride and4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 446; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.72 (quin, J=6.06 Hz, 2H)2.21 (s, 3H) 2.30 (s, 3H) 2.90 (d, J=5.05 Hz, 2H) 3.49 (q, J=6.32 Hz,2H) 3.44-3.52 (m, 2H) 5.33-5.43 (m, 1H) 5.57 (br. s., 2H) 5.78 (s, 1H)7.05-7.09 (m, 1H) 7.09-7.13 (m, 1H) 7.16-7.20 (m, 1H) 7.41-7.46 (m, 2H)7.79-7.84 (m, 2H).

Example 3583-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-1-(4-chlorophenyl)urea

Prepared according to general procedure 11 from1-chloro-4-isocyanatobenzene and4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 425; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 1.85 (t, J=6.69 Hz, 2H)2.23 (s, 3H) 2.34 (s, 3H) 3.28 (overlap with methanol) 3.50-3.61 (m, 2H)5.97 (s, 1H) 7.15 (s, 1H) 7.17-7.25 (m, 3H) 7.28-7.37 (m, 3H).

Example 359N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3,5-dimethyl-1,2-oxazole-4-sulfonamide

Prepared according to general procedure 10 fromdimethyl-1,2-oxazole-4-sulfonyl chloride and4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine.

LCMS [M+H]⁺ 431; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.79 (br. quin, J=6.0Hz, 2H) 2.23 (s, 3H) 2.30 (s, 3H) 2.42 (s, 3H) 2.64 (s, 3H) 3.01 (br. q,J=5.90 Hz, 2H) 3.53 (br. q, J=6.00 Hz, 2H) 5.89 (s, 1H) 7.05-7.13 (m,2H) 7.18-7.21 (m, 1H).

Example 360N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-2-(dimethylamino)acetamide

In a vial4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (10 mg,0.037 mmol) and 2-(dimethylamino)acetyl chloride hydrochloride (50 mg,0.32 mmol) were suspended in DCM (1.0 ml), then Et₃N (0.013 ml, 0.092mmol) was added. The resulting reaction mixture was stirred at r.t. for1 h. Then MeOH was added and the mixture was stirred 30 min after whichthe mixture was concentrated and purified by preparative HPLC. LCMS[M+H]⁺ 357; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.70-1.78 (m, 2H) 2.28 (s,3H) 2.31 (s, 3H) 2.35 (s, 6H) 3.06 (s, 2H) 3.34-3.41 (m, 2H) 3.48-3.55(m, 2H) 5.85 (s, 1H) 7.12-7.16 (m, 2H) 7.17-7.22 (m, 1H).

Example 3613-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-1-(2,6-dichloropyridin-4-yl)urea

Prepared according to general procedure 11 from2,6-dichloro-4-isocyanatopyridine and4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 460; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.86 (br. quint, J=6.7 Hz,2H) 2.24 (s, 3H) 2.34 (s, 3H) 3.30-3.34 (m [overlap w MeOH], 2H) 3.55(br. s., 3H) 5.98 (s, 1H) 7.11-7.24 (m, 2H) 7.27-7.33 (m, 1H) 7.46 (s,2H).

Example 3623-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-1-(3,4-difluorophenyl)urea

Prepared according to general procedure 11 from1,2-difluoro-4-isocyanatobenzene and4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 427; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.81-1.89 (m, 2H) 2.24 (s,3H) 2.34 (s, 3H) 3.25-3.30 (m [overlap w MeOH], 2H) 3.55 (br. s., 2H)5.98 (s, 1H) 6.94-7.01 (m, 1H) 7.06-7.17 (m, 2H) 7.17-7.23 (m, 1H)7.27-7.33 (m, 1H) 7.45-7.54 (m, 1H).

Example 363N-[3-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propoxy)phenyl]acetamide

Prepared according to general procedure 9 fromN-[3-(3-aminopropoxy)phenyl]acetamide and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 406; ¹HNMR (400 MHz, DMSO-d₆) δ_(H) ppm 1.96 (t, J=6.32 Hz, 2H) 2.02 (s, 3H)2.15 (s, 3H) 2.25 (s, 3H) 4.00 (t, J=6.32 Hz, 2H) 5.70 (s, 1H) 5.92 (br.s., 2H) 6.61 (dd, J=8.46, 1.64 Hz, 1H) 6.85-6.99 (m, 1H) 6.99-7.10 (m,3H) 7.11-7.19 (m, 2H) 7.31 (s, 1H) 9.88 (s, 1H). A signal from one ofthe CH₂-groups is overlapping with solvent peaks and is not observed byNMR.

Example 3646-(2,3-Dimethylphenyl)-4-N-[(2-methyl-1H-indol-5-yl)methyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from(2-methyl-1H-indol-5-yl)methanamine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 358; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 2.22 (s, 3H) 2.29 (s, 3H) 2.45 (d, J=0.76Hz, 3H) 4.57 (br. s., 2H) 5.16-5.32 (m, 2H) 5.85 (s, 1H) 6.18-6.21 (m,1H) 7.05-7.15 (m, 3H) 7.15-7.19 (m, 1H) 7.24-7.28 (m, 1H) 7.47 (s, 1H)7.97 (br. s., 1H).

Example 3654-N-[2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from2-(3,5-dimethyl-1H-pyrazol-1-yl)ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 337; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 2.17 (d, J=0.51 Hz, 3H) 2.18 (s, 3H) 2.21(s, 3H) 2.29 (s, 3H) 2.51-2.63 (m, 1H) 3.68-3.76 (m, 2H) 4.13 (t, J=5.56Hz, 2H) 5.03 (s, 2H) 5.37-5.47 (m, 1H) 5.71 (s, 1H) 5.77 (s, 1H)7.07-7.12 (m, 2H) 7.12-7.17 (m, 1H).

Example 3666-(2,3-Dimethylphenyl)-4-N-[4-(pyrrolidin-1-yl)butyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from4-(pyrrolidin-1-yl)butan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 340; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 1.60-1.73 (m, 4H) 1.78-1.86 (m, 4H) 2.24(s, 3H) 2.31 (s, 3H) 2.49-2.60 (m, 6H) 3.31 (br. s., 2H) 4.79 (s, 2H)5.46-5.58 (m, 1H) 5.78 (s, 1H) 7.09-7.18 (m, 3H).

Example 367N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3-bromobenzamide

4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (1.0eq) was dissolved in THF (0.50 mL) and NMP (0.050 mL), then Et₃N (1.5eq) and 3-bromobenzoyl chloride (1.2 eq) were added. The resultingreaction mixture was stirred at rt overnight. The mixture was thenconcentrated and purified by column chromatography. LCMS [M+H]⁺ 454; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 1.80-1.89 (m, 2H) 2.23 (s, 3H) 2.30 (s,3H) 2.37-2.59 (m, 1H) 3.47-3.58 (m, 4H) 5.14 (br. s., 2H) 5.55-5.69 (m,1H) 5.85 (s, 1H) 7.07-7.13 (m, 2H) 7.17 (dd, J=6.19, 2.91 Hz, 1H) 7.31(t, J=7.83 Hz, 1H) 7.63 (ddd, J=7.89, 1.96, 1.01 Hz, 1H) 7.75 (dd,J=7.83, 1.01 Hz, 1H) 7.98 (t, J=1.77 Hz, 1H).

Example 368N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)benzamide

In a vial4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (1.0eq) was dissolved in NMP (0.050 mL) and THF (0.50 mL), then Et₃N (1.5eq) and benzoyl chloride (1.0 eq) were added. The resulting reactionmixture was stirred at rt for 1 h. The mixture was then concentrated andpurified by column chromatography. LCMS [M+H]⁺ 376; ¹H NMR (400 MHz,CDCl₃) δ ppm 1.86 (t, J=6.06 Hz, 2H) 2.22 (s, 3H) 2.29 (s, 3H) 3.54 (dt,J=12.32, 6.09 Hz, 4H) 5.36-5.54 (m, 1H) 5.89 (s, 1H) 6.14-6.31 (m, 1H)7.06-7.13 (m, 2H) 7.16-7.20 (m, 1H) 7.40-7.46 (m, 2H) 7.47-7.53 (m, 1H)7.80-7.85 (m, 2H).

Example 3691-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3-(propan-2-yl)urea

Prepared according to general procedure 11 from 2-isocyanatopropane and4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 357; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.12 (d, J=6.57 Hz, 6H)1.78 (t, J=6.69 Hz, 2H) 2.24 (s, 3H) 2.35 (s, 3H) 3.20 (t, J=6.82 Hz,2H) 3.45-3.57 (m, 2H) 3.74-3.85 (m, 1H) 5.97 (s, 1H) 7.19 (d, J=14.65Hz, 2H) 7.30 (s, 1H).

Example 370 tert-ButylN-(4-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}butyl)-carbamate

Prepared according to general procedure 9 from tert-butylN-(4-aminobutyl)carbamate. LCMS [M+H]⁺ 386; ¹H NMR (400 MHz, CDCl₃)δ_(H) ppm 1.45 (s, 9H) 1.54-1.72 (m, 6H) 2.24-2.28 (m, 3H) 2.31 (s, 3H)3.20 (d, J=6.32 Hz, 3H) 3.33-3.43 (m, 2H) 4.79-4.91 (m, 1H) 5.79-5.83(m, 1H) 7.14 (s, 2H) 7.16-7.21 (m, 1H).

Example 371 tert-ButylN-(5-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}pentyl)-carbamate

Step 1: 4-N-(5-Aminopentyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diaminewas prepared according to general procedure 9 from pentane-1,5-diamineand 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine.

Step 2: 4-N-(5-Aminopentyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine(15 mg, 0.028 mmol) and tert-butoxycarbonyl tert-butyl carbonate (7.2mg, 0.033 mmol) were dissolved in THF (0.50 mL). Then Et₃N (0.011 mL,0.085 mmol) was added and the resulting mixture was stirred at roomtemperature for 16 h. The reaction mixture was concentrated and purifiedby column chromatography (0→5% in DCM) to afford tert-butylN-[5-[[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino]pentyl]carbamate.LCMS [M+H]⁺ 400; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.35-1.47 (m, 11H)1.52 (d, J=7.07 Hz, 2H) 1.58-1.68 (m, 2H) 2.24 (s, 3H) 2.29 (s, 3H) 3.13(d, J=6.06 Hz, 2H) 3.26-3.37 (m, 2H) 4.58-4.68 (m, 1H) 5.89 (s, 1H) 7.11(d, J=4.80 Hz, 2H) 7.18 (d, J=4.80 Hz, 1H).

Example 372 tert-ButylN-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}cyclohexyl)-carbamate

Step 1:4-N-(2-Aminocyclohexyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine wasprepared according to general procedure 9 from cyclohexane-1,2-diamineand 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine.

Step 2:4-N-(2-Aminocyclohexyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (15mg, 0.028 mmol) and tert-butoxycarbonyl tert-butyl carbonate (7.0 mg,0.032 mmol) were dissolved in THF (0.50 mL). Then Et₃N (0.0050 mL, 0.036mmol) was added and the resulting mixture was stirred at rt for 16 h.The reaction mixture was concentrated and purified by columnchromatography (0-→5% in DCM) to afford tert-butylN-[2-[[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino]cyclohexyl]carbamate.LCMS [M+H]⁺ 412; NMR: mixture of cis- and trans-diastereomers: ¹H NMR(400 MHz, CDCl₃) δ_(H) ppm 1.16-1.37 (m, 6H) 1.38-1.42 (m, 18H) 1.53(br. s., 6H) 1.79 (br. s., 4H) 2.00-2.08 (m, 1H) 2.18-2.23 (m, 1H) 2.25(d, J=3.79 Hz, 6H) 2.31 (s, 6H) 3.40-3.51 (m, 1H) 3.62-3.75 (m, 1H)3.83-3.92 (m, 1H) 3.97-4.10 (m, 1H) 4.80-4.93 (m, 1H) 4.97-5.10 (m, 1H)5.15-5.37 (m, 2H) 5.43-5.67 (m, 2H) 5.75 (s, 1H) 5.83 (s, 1H) 7.09-7.15(m, 4H) 7.16-7.21 (m, 2H).

Example 373 tert-ButylN-(1-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-2-methylpropan-2-yl)carbamate

Step 1:4-N-(2-Amino-2-methyl-propyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diaminewas prepared according to general procedure 9 from2-methylpropane-1,2-diamine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine.

Step 2:4-N-(2-Amino-2-methylpropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine(15 mg, 0,029 mmol) and tert-butoxycarbonyl tert-butyl carbonate (7.8mg, 0.036 mmol) were dissolved in THF (0.50 mL). Then Et₃N (0.0061 mL,0.044 mmol) was added and the resulting mixture was stirred at rt for 16h. The reaction mixture was concentrated and purified by columnchromatography (0-→5% in DCM) to afford tert-butylN-[2-[[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino]-1,1-dimethyl-ethyl]carbamate.LCMS [M+H]⁺ 386; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.34 (s, 6H) 1.43 (s,9H) 2.26 (s, 3H) 2.31 (s, 3H) 3.53 (d, J=5.81 Hz, 2H) 5.14-5.47 (m, 2H)5.87 (s, 1H) 7.10-7.16 (m, 2H) 7.18 (d, J=3.28 Hz, 1H).

Example 374N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3-cyanobenzene-1-sulfonamide

Prepared according to general procedure 10 from3-cyanobenzene-1-sulfonyl chloride and4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 437; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.70-1.82 (m, 4H) 2.23 (s,3H) 2.31 (s, 3H) 2.98 (d, J=5.31 Hz, 2H) 3.54 (d, J=5.81 Hz, 2H)4.71-4.80 (m, 1H) 5.29 (br. s., 2H) 5.76 (s, 1H) 7.07-7.21 (m, 3H)7.59-7.65 (m, 1H) 7.82 (dt, J=7.64, 1.36 Hz, 1H) 8.14 (dq, J=7.96, 0.97Hz, 1H) 8.18-8.21 (m, 1H).

Example 375N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-4-methanesulfonylbenzene-1-sulfonamide

Prepared according to general procedure 10 from4-methanesulfonylbenzene-1-sulfonyl chloride and4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 490; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.73-1.80 (m, 2H) 2.23 (s,3H) 2.32 (s, 3H) 2.95-3.01 (m, 2H) 3.08 (s, 3H) 3.51-3.58 (m, 2H)4.69-4.77 (m, 1H) 5.31 (s, 2H) 5.77 (s, 1H) 7.08-7.21 (m, 3H) 8.09 (q,J=8.76 Hz, 4H).

Example 376N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)benzenesulfonamide

Prepared according to general procedure 10 from benzenesulfonyl chlorideand 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine.LCMS [M+H]⁺ 412; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.72 (dt, J=12.06, 5.97Hz, 2H) 1.76-1.89 (m, 1H) 2.22 (s, 3H) 2.31 (s, 3H) 2.93 (q, J=6.15 Hz,2H) 3.49 (q, J=6.40 Hz, 2H) 4.70-4.82 (m, 1H) 5.28 (br. s., 2H)5.72-5.74 (m, 1H) 7.08-7.15 (m, 2H) 7.16-7.20 (m, 1H) 7.45-7.51 (m, 2H)7.52-7.57 (m, 1H) 7.87-7.92 (m, 2H).

Example 377N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-2,2-dimethylpropyl)-3-fluorobenzene-1-sulfonamide

Step 1: tert-butylN-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-2,2-dimethylpropyl)carbamate(prepared in example 239) (180 mg, 0.45 mmol) was dissolved intrifluoroacetic acid (2 ml) and stirred at reflux for 1 h. The TFA wasevaporated and the crude residue was purified by silica gelchromatography using a gradient of 2-30% MeOH [containing 1 v/v % NH4OH]in DCM which afforded4-N-(3-amino-2,2-dimethyl-propyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine(110 mg, 0.37 mmol). LCMS [M+H]⁺ 300.

Step 2:N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-2,2-dimethylpropyl)-3-fluorobenzene-1-sulfonamidewas prepared according to general procedure 10 from3-fluorobenzene-1-sulfonyl chloride and4-N-(3-amino-2,2-dimethyl-propyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine(prepared in step 1). LCMS [M+H]⁺ 458; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm0.92 (s, 6H) 2.16-2.20 (m, 3H) 2.29 (s, 3H) 2.69 (d, J=7.07 Hz, 2H) 3.38(d, J=6.82 Hz, 2H) 5.91 (s, 1H) 6.53 (s, 1H) 7.04-7.08 (m, 1H) 7.09-7.15(m, 1H) 7.23-7.30 (m, 1H) 7.38-7.45 (m, 1H) 7.46-7.56 (m, 2H) 7.64 (d,J=7.83 Hz, 1H).

Example 378N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-2,2-dimethylpropyl)-4-(morpholine-4-sulfonyl)benzene-1-sulfonamide

Step 1: tert-butylN-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-2,2-dimethylpropyl)carbamate(prepared in example 239) (180 mg, 0.45 mmol) was dissolved intrifluoroacetic acid (2 ml) and stirred at reflux for 1 h. The TFA wasevaporated and the crude residue was purified by silica gelchromatography using a gradient of 2-30% MeOH [containing 1 v/v % NH4OH]in DCM which afforded4-N-(3-amino-2,2-dimethyl-propyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine(110 mg, 0.37 mmol). LCMS [M+H]⁺ 300.

Step 2:N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-2,2-dimethylpropyl)-4-(morpholine-4-sulfonyl)benzene-1-sulfonamidewas prepared according to general procedure 10 from4-(morpholine-4-sulfonyl)benzene-1-sulfonyl chloride and4-N-(3-amino-2,2-dimethyl-propyl)-6-(2,3-dimethyl-phenyl)pyrimidine-2,4-diamine(prepared in step 1 above). LCMS [M+H]⁺ 589; ¹H NMR (400 MHz, CDCl₃)δ_(H) ppm 0.92 (s, 6H) 2.18 (d, J=0.51 Hz, 3H) 2.28 (s, 3H) 2.71 (d,J=6.82 Hz, 2H) 2.99-3.06 (m, 4H) 3.38 (d, J=6.82 Hz, 2H) 3.70-3.78 (m,4H) 5.93 (s, 1H) 6.94 (s, 1H) 7.03-7.08 (m, 1H) 7.09-7.15 (m, 1H) 7.25(d, J=7.58 Hz, 1H) 7.42 (s, 1H) 7.87 (d, J=8.59 Hz, 2H) 8.02 (d, J=8.59Hz, 2H).

Example 3796-(2,3-Dimethylphenyl)-4-N-(prop-2-en-1-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from prop-2-en-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 255; ¹HNMR (400 MHz, CDCl₃) δ_(H) ppm 2.23 (s, 3H) 2.31 (s, 3H) 3.92 (br. s.,2H) 4.95 (br. s., 3H) 5.18 (dq, J=10.23, 1.47 Hz, 1H) 5.26 (dq, J=17.18,1.60 Hz, 1H) 5.81 (s, 1H) 5.85-5.96 (m, 1H) 7.10-7.15 (m, 2H) 7.15-7.19(m, 1H).

Example 3801-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)imidazolidin-2-one

Prepared according to general procedure 9 from1-(3-aminopropyl)imidazolidin-2-one and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 341.

Example 381N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3-fluorobenzene-1-sulfonamide

Prepared according to general procedure 9 from3-fluorobenzene-1-sulfonyl chloride and4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine.

LCMS [M+H]⁺ 430.

Example 382N-{4-[(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)sulfamoyl]-phenyl}acetamide

Prepared according to general procedure 10 from4-acetamidobenzene-1-sulfonyl chloride and4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 469.

Example 383N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)methanesulfonamide

Prepared according to general procedure 10 from methanesulfonyl chlorideand 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine.LCMS [M+H]⁺ 350.

Example 384N-(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-3-fluorobenzene-1-sulfonamide

Prepared according to general procedure 10 from3-fluorobenzene-1-sulfonyl chloride and4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 416.

Example 385N-(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-4-methoxybenzene-1-sulfonamide

Prepared according to general procedure 10 from4-methoxybenzene-1-sulfonyl chloride and4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 428.

Example 3866-(2,3-Dimethylphenyl)-4-N-(prop-2-yn-1-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from prop-2-yn-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 253.

Example 3872-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}acetamide

Prepared according to general procedure 9 from 2-aminoacetamide and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 272.

Example 388N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-4,5-dichlorothiophene-2-sulfonamide

Prepared according to general procedure 10 from4,5-dichlorothiophene-2-sulfonyl chloride and4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 486.

Example 389N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide

Prepared according to general procedure 10 from5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride and4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)-pyrimidine-2,4-diamine. LCMS[M+H]⁺ 464.

Example 3902-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}acetonitrile

Prepared according to general procedure 9 from 2-aminoacetonitrile and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 254.

Example 391N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-1,2-dimethyl-1H-imidazole-4-sulfonamide

Prepared according to general procedure 10 from1,2-dimethyl-1H-imidazole-4-sulfonyl chloride and4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 430; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.69 (s, 2H), 7.33-7.38(m, 1H), 7.21-7.27 (m, 1H), 7.16-7.20 (m, 1H), 6.00 (s, 1H), 3.71 (s,3H), 3.58 (s, 2H), 3.06 (s, 2H), 2.45 (s, 3H), 2.36 (s, 3H), 2.25 (s,3H), 1.80-1.90 (m, 2H).

Example 392N-(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide

Prepared according to general procedure 10 from5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride and4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)-pyrimidine-2,4-diamine. LCMS[M+H]⁺ 450.

Example 393 4-N-{2-[(1,3-Benzoxazol-2-yl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 12 from 2-chloro-1,3-benzoxazoleand 4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine.LCMS [M+H]⁺ 375.

Example 3946-(2,3-Dimethylphenyl)-4-N-(4-phenylbutan-2-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 4-phenylbutan-2-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 347.

Example 3954-N-(2,2-Dimethyloxan-4-yl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 2,2-dimethyloxan-4-amineand 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 327.

Example 396 Ethyl2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}acetate

Prepared according to general procedure 9 from ethyl 2-aminoacetate and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 301.

Example 3976-[(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)amino]pyridine-3-carbonitrile

Prepared according to general procedure 12 from6-chloropyridine-3-carbonitrile and4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 360; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 8.32-8.34 (m, 1H),7.59-7.64 (m, 1H), 7.34-7.38 (m, 1H), 7.22-7.27 (m, 2H), 7.15-7.18 (m,1H), 6.55-6.59 (m, 1H), 5.97 (s, 1H), 3.72-3.77 (m, 3H), 3.66-3.71 (m,3H), 2.36 (s, 4H), 2.24 (s, 3H).

Example 3984-N-{2-[(3-Bromo-1,2,4-thiadiazol-5-yl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 12 from3-bromo-5-chloro-1,2,4-thiadiazole and4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 420.

Example 3996-(2,3-Dimethylphenyl)-4-N-[(5-methyl-4H-1,2,4-triazol-3-yl)methyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from(5-methyl-4H-1,2,4-triazol-3-yl)methanamine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 310; ¹HNMR (400 MHz, CD₃OD) δ_(H) ppm 7.37-7.41 (m, 1H), 7.25-7.30 (m, 1H),7.20-7.24 (m, 1H), 6.12 (s, 1H), 4.79 (s, 2H), 2.47 (s, 3H), 2.38 (s,3H), 2.29 (s, 3H).

Example 4006-(2,3-Dimethylphenyl)-4-N-{2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]ethyl}pyrimidine-2,4-diamine

Prepared according to general procedure 9 from2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]ethan-1-amine and4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 405.

Example 401N-(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-4-methanesulfonylbenzene-1-sulfonamide

Prepared according to general procedure 10 from4-methanesulfonylbenzene-1-sulfonyl chloride and4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 476; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 8.10-8.14 (m, 3H),8.05-8.09 (m, 3H), 7.16-7.20 (m, 1H), 7.09-7.14 (m, 1H), 7.05-7.08 (m,1H), 5.73-5.76 (m, 1H), 3.42-3.49 (m, 2H), 3.14 (s, 6H), 2.31 (s, 4H),2.18 (s, 3H).

Example 402N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3-methanesulfonylbenzene-1-sulfonamide

Prepared according to general procedure 10 from3-methanesulfonylbenzene-1-sulfonyl chloride and4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 490; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 8.43-8.45 (m, 1H), 8.18(ddd, J=7.8, 1.8, 1.0 Hz, 3H), 8.11 (ddd, J=7.8, 1.8, 1.0 Hz, 3H),7.67-7.73 (m, 1H), 7.15-7.19 (m, 1H), 7.09-7.13 (m, 1H), 7.08 (d, J=2.0Hz, 1H), 5.74 (s, 1H), 5.31 (br. s., 2H), 4.82-5.00 (m, 1H), 3.50 (d,J=5.8 Hz, 2H), 3.09 (s, 3H), 2.94 (d, J=4.0 Hz, 2H), 2.29 (s, 3H), 2.20(s, 3H), 1.71 (t, J=5.8 Hz, 2H).

Example 403N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-2-methanesulfonylbenzene-1-sulfonamide

Prepared according to general procedure 10 from2-methanesulfonylbenzene-1-sulfonyl chloride and4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS[M+H]⁺ 490; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 8.20-8.33 (m, 3H),8.10-8.17 (m, 1H), 7.84-7.90 (m, 5H), 7.68-7.80 (m, 3H), 7.16-7.21 (m,3H), 7.12 (s, 3H), 7.08 (d, J=1.5 Hz, 3H), 5.74 (s, 3H), 3.46 (s, 3H),3.43 (s, 8H), 3.32-3.36 (m, 3H), 3.07 (t, J=6.7 Hz, 5H), 2.31 (s, 8H),2.19 (s, 3H), 1.66 (t, J=6.7 Hz, 5H).

Example 4046-(2,3-Dimethylphenyl)-4-N-[2-(4-methanesulfonylphenyl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.15mmol), 2-(4-methylsulfonylphenyl)ethanamine (1.2 eq.) andN,N-diisopropylethylamine (2.25 eq.) in n-butanol (0.3 mL) was heated ina sealed tube at 110° C. overnight. Methanol was added and the mixturewas filtered and purified by preparative HPLC. LCMS [M+H]⁺ 397.

Example 4056-(2,3-dichlorophenyl)-4-N-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (0.08mmol), 2-(4-methylthiazol-5-yl)ethanamine; dihydrobromide (1.2 eq.) andN,N-diisopropylethylamine (4.25 eq.) in n-butanol (0.3 ml) was heated ina sealed tube at 110° C. overnight. Methanol was added and the mixturewas filtered and purified by preparative HPLC. LCMS [M+H]⁺ 380.

Example 4066-(3-chloro-2-methylphenyl)-4-N-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(3-chloro-2-methyl-phenyl)pyrimidin-2-amine(0.14 mmol), 2-(4-methylthiazol-5-yl)ethanamine; dihydrobromide (1.2eq.) and N,N-diisopropylethylamine (4.25 eq.) in n-butanol (0.3 mL) washeated in a sealed tube at 110° C. overnight. Methanol was added and themixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 360.

Example 4074-N-{[2-(difluoromethyl)pyridin-4-yl]methyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.13mmol), [2-(difluoromethyl)-4-pyridyl]methanamine; hydrochloride (1.2eq.) and N,N-diisopropylethylamine (3.25 eq.) in n-butanol (0.3 ml) washeated in a sealed tube at 110° C. overnight. Methanol was added and themixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 356.

Example 4086-(2,3-dimethylphenyl)-4-N-[2-(1H-imidazol-4-yl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.13mmol), 2-(1H-imidazol-4-yl)ethanamine; dihydrochloride (1.2 eq.) andN,N-diisopropylethylamine (3.25 eq.) in n-butanol (0.3 mL) was heated ina sealed tube at 110° C. overnight. Methanol was added and the mixturewas filtered and purified by preparative HPLC. LCMS [M+H]⁺ 309.

Example 4094-N-[3-(1H-1,3-benzodiazol-2-yl)propyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.13mmol), 3-(1H-benzimidazol-2-yl)propan-1-amine (1.2 eq.) andN,N-diisopropylethylamine (3.25 eq.) in n-butanol (0.3 mL) was heated ina sealed tube at 110° C. overnight. Methanol was added and the mixturewas filtered and purified by preparative HPLC. LCMS [M+H]⁺ 373.

Example 4106-(2,3-dimethylphenyl)-4-N-[(1-methyl-1H-1,3-benzodiazol-2-yl)methyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.14mmol), (1-methylbenzimidazol-2-yl)methanamine (1.2 eq.) andN,N-diisopropylethylamine (1.25 eq.) in n-butanol (0.3 mL) was heated ina sealed tube at 110° C. overnight. Methanol was added and the mixturewas filtered and purified by preparative HPLC. LCMS [M+H]⁺ 359.

Example 4116-(2,3-dimethylphenyl)-4-N-[(2-phenyl-1,3-thiazol-5-yl)methyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.13mmol), (2-phenylthiazol-5-yl)methanamine hydrochloride (1.2 eq.) andN,N-diisopropylethylamine (2.25 eq.) in n-butanol (0.3 mL) was heated ina sealed tube at 110° C. overnight. Methanol was added and the mixturewas filtered and purified by preparative HPLC. LCMS [M+H]⁺ 388.

Example 4126-(3-chloro-2-methylphenyl)-4-N-[2-(5-methyl-1H-1,2,4-triazol-3-yl)ethyl]pyrimidine-2,4-diamine

A mixture 4-chloro-6-(3-chloro-2-methyl-phenyl)pyrimidin-2-amine (0.14mmol), 2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanamine hydrochloride (1.2eq.) and N, N-diisopropylethylamine (3.25 eq.) in n-butanol (0.3 mL) washeated in a sealed tube at 110° C. overnight. Methanol was added and themixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 344.

Example 4136-(2,3-dichlorophenyl)-4-N-[2-(5-methyl-1H-1,2,4-triazol-3-yl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (0.13mmol), 2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanamine hydrochloride (1.0eq.) and N, N-diisopropylethylamine (3.25 eq.) in n-butanol (0.3 mL) washeated in a sealed tube at 110° C. overnight. Methanol was added and themixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 364.

Example 4144-(2-{[2-amino-6-(3-chloro-2-methylphenyl)pyrimidin-4-yl]amino}ethyl)-N,N-dimethylbenzene-1-sulfonamide

A mixture of 4-chloro-6-(3-chloro-2-methyl-phenyl)pyrimidin-2-amine(0.14 mmol), 4-(2-aminoethyl)-N,N-dimethyl-benzenesulfonamide (1.0 eq.)and N,N-diisopropylethylamine (2.25 eq.) in n-butanol (0.3 mL) washeated in a sealed tube at 110° C. overnight. Methanol was added and themixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 446.

Example 4154-(2-{[2-amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}ethyl)-N,N-dimethylbenzene-1-sulfonamide

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (0.13mmol), 4-(2-aminoethyl)-N, N-dimethyl-benzenesulfonamide (1.0 eq.) andN,N-diisopropylethylamine (2.25 eq.) in n-butanol (0.3 mL) was heated ina sealed tube at 110° C. overnight. Methanol was added and the mixturewas filtered and purified by preparative HPLC. LCMS [M+H]⁺ 466.

Example 4164-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-N,N-dimethylbenzene-1-sulfonamide

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.15mmol), 4-(2-aminoethyl)-N, N-dimethyl-benzenesulfonamide (1.0 eq.) andN,N-diisopropylethylamine (2.25 eq.) in n-butanol (0.3 mL) was heated ina sealed tube at 110° C. overnight. Methanol was added and the mixturewas filtered and purified by preparative HPLC. LCMS [M+H]⁺ 426.

Example 4174-N-{1-[(4-Chlorophenyl)methyl]cyclopropyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (47 mg,0.20 mmol), 1-[(4-chlorophenyl)methyl]cyclopropan-1-amine hydrochloride(52 mg, 0.24 mmol) and triethylamine (50 μL, 0.36 mmol) in n-butanol (3mL) was heated in a sealed tube at 130° C. overnight. The reactionmixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺379.

Example 4184-N-Cyclopropyl-6-(2,3,4-trichlorophenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3,4-trichlorophenyl)pyrimidin-2-amine (21 mg,0.050 mmol), cyclopropanamine (25 μL, 0.36 mmol) and triethylamine (25μL, 0.18 mmol) in n-butanol (1.5 mL) was heated in a sealed tube at 90°C. overnight. The reaction mixture was concentrated and purified bypreparative HPLC. LCMS [M+H]⁺ 329.

Example 4194-N-[2-(4-Chlorophenyl)ethyl]-6-(2,3,4-trichlorophenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3,4-trichlorophenyl)pyrimidin-2-amine (21 mg,0.050 mmol), 2-(4-chlorophenyl)ethan-1-amine (30 μL, 0.24 mmol) andtriethylamine (25 μL, 0.18 mmol) in n-butanol (1.5 mL) was heated in asealed tube at 90° C. overnight. The reaction mixture was concentratedand purified by preparative

HPLC. LCMS [M+H]⁺ 427.

Example 420 6-(2,3-dimethylphenyl)-4-N—(²H₃)methylpyrimidine-2,4-diamine

A solution of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.15mmol) and d₃-methanamine hydrochloride (70 mg; 1 mmol) and triethylamine(101 mg; 1 mmol) in n-BuOH (2.0 mL) was heated at 95° C. overnight. Thereaction mixture was concentrated and purified by preparative HPLC. LCMS[M+H]⁺ 232.

Example 421 6-(2,3-dichlorophenyl)-4-N—(²H₃)methylpyrimidine-2,4-diamine

A solution of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (0.15mmol) and d₃-methanamine hydrochloride (70 mg; 1 mmol) and triethylamine(101 mg; 1 mmol) in n-BuOH (2.0 mL) was heated at 95° C. overnight. Thereaction mixture was concentrated and purified by preparative HPLC toafford the product. LCMS [M+H]⁺ 272.

Example 4226-(2-chloro-3-methylphenyl)-4-N—(²H₃)methylpyrimidine-2,4-diamine

A solution of 4-chloro-6-(2-chloro-3-methylphenyl)pyrimidin-2-amine(0.15 mmol) and d₃-methanamine hydrochloride (70 mg; 1 mmol) andtriethylamine (101 mg; 1 mmol) in n-BuOH (2.0 mL) was heated at 95° C.overnight. The reaction mixture was concentrated and purified bypreparative HPLC to afford the product. LCMS [M+H]⁺ 252.

Example 4234-N-[2-(4-Chlorophenyl)ethyl]-6-(1H-pyrrol-2-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 10 from6-chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine and(1-tert-butoxycarbonylpyrrol-2-yl)boronic acid. The t-butoxycarbonylgroup was removed during work-up. LCMS [M+H]⁺ 314; ¹H NMR (400 MHz,CD₃OD) δ_(H) ppm 7.29-7.33 (m, 5H), 7.27 (s, 2H), 7.10-7.13 (m, 1H),6.88-6.92 (m, 1H), 6.33-6.37 (m, 1H), 6.12 (s, 1H), 3.70-3.76 (m, 2H),2.91-2.96 (m, 2H).

Example 424N-(4-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}butyl)-4-methanesulfonylbenzene-1-sulfonamide

Prepared according to general procedure 10 from4-(methylsulfonyl)-benzenesulfonyl chloride and4-N-(4-aminobutyl)-6-(2,3-dimethylphenyl)-pyrimidine-2,4-diamine. LCMS[M+H]⁺ 504; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 8.12-8.17 (m, 2H),8.06-8.10 (m, 2H), 7.16-7.20 (m, 1H), 7.09-7.14 (m, 1H), 7.05-7.09 (m,1H), 5.76-5.79 (m, 1H), 3.18 (s, 3H), 2.94-2.99 (m, 2H), 2.31 (s, 3H),2.19 (s, 3H), 1.50-1.66 (m, 4H).

Example 4254-(2-{[2-amino-6-(4-fluoro-2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 2 from4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzenesulfonamideand 4-fluoro-2,3-dimethyl-benzeneboronic acid. LCMS [M+H]⁺ 416; ¹H NMR(400 MHz, CD₃OD) δ_(H) ppm 7.81-7.85 (m, 2H), 7.44 (d, J=8.6 Hz, 2H),7.07 (dd, J=8.5, 5.9 Hz, 1H), 6.92 (t, J=8.8 Hz, 1H), 5.75 (s, 1H), 3.63(br. s., 2H), 2.99 (t, J=7.2 Hz, 2H), 2.20-2.23 (m, 6H).

Example 426 4-(2-{[2-amino-6-(3-cyano-2-methylphenyl)pyri midin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 2 from4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzenesulfonamideand 3-cyano-2-methyl-benzeneboronic acid. LCMS [M+H]⁺ 409; ¹H NMR (400MHz, CD₃OD) δ_(H) ppm 7.80-7.86 (m, 2H), 7.70 (dd, J=7.8, 1.3 Hz, 1H),7.53 (d, J=6.8 Hz, 1H), 7.37-7.47 (m, 3H), 5.80 (s, 1H), 3.65 (br. s.,2H), 3.00 (t, J=7.2 Hz, 2H), 2.49 (s, 3H).

Example 4274-(2-{[2-amino-6-(5-chloro-2-methylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 2 from4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzenesulfonamideand 5-chloro-2-methyl-benzeneboronic acid. LCMS [M+H]⁺ 418; ¹H NMR (400MHz, CD₃OD) δ_(H) ppm 7.81-7.85 (m, 2H), 7.44 (d, J=8.3 Hz, 2H),7.21-7.29 (m, 3H), 5.80 (s, 1H), 3.64 (br. s., 2H), 2.99 (t, J=7.2 Hz,2H), 2.28 (s, 3H).

Example 4284-(2-{[2-amino-6-(3,4-dichloro-2-methylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 2 from4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzenesulfonamideand 3,4-dichloro-2-methyl-benzeneboronic acid. LCMS [M+H]⁺ 452; ¹H NMR(400 MHz, CDCl₃) δ_(H) ppm 7.88 (d, J=8.3 Hz, 2H), 7.38 (d, J=8.3 Hz,2H), 7.33-7.36 (m, 1H), 7.15 (s, 1H), 5.73 (s, 1H), 4.87 (s, 2H),4.81-4.84 (m, 2H), 4.70-4.77 (m, 1H), 3.61-3.69 (m, 2H), 3.01 (s, 2H),2.41 (s, 3H).

Example 4296-(3-chloro-2-methylphenyl)-4-N-(prop-2-yn-1-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 7 from propargylamine and4-chloro-6-(3-chloro-2-methyl-phenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 273;¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.40-7.43 (m, 1H), 7.21 (s, 2H),5.85-5.88 (m, 1H), 4.13-4.18 (m, 2H), 2.59 (s, 1H), 2.33 (s, 3H).

Example 4306-(4-fluoro-2,3-dimethylphenyl)-4-N-[2-(4-methanesulfonylphenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from6-chloro-4-N-[2-(4-methylsulfonylphenyl)ethyl]pyrimidine-2,4-diamine and4-fluoro-2,3-dimethyl-benzeneboronic acid. LCMS [M+H]⁺ 415; ¹H NMR (400MHz, CD₃OD) δ_(H) ppm 7.88 (s, 2H), 7.53-7.58 (m, 2H), 7.06-7.11 (m,1H), 6.91-6.97 (m, 1H), 5.76 (s, 1H), 3.64-3.72 (m, 2H), 3.11 (s, 3H),3.02-3.08 (m, 2H), 2.22-2.25 (m, 6H).

Example 4316-(3,4-dichloro-2-methylphenyl)-4-N-[2-(4-methanesulfonylphenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from6-chloro-4-N-[2-(4-methylsulfonylphenyl)ethyl]pyrimidine-2,4-diamine and3,4-dichloro-2-methyl-benzeneboronic acid. LCMS [M+H]⁺ 451; ¹H NMR (400MHz, CD₃OD) δ_(H) ppm 7.89 (d, J=8.6 Hz, 2H), 7.57 (s, 2H), 7.43-7.46(m, 1H), 7.17-7.21 (m, 1H), 5.78 (s, 1H), 3.63-3.75 (m, 2H), 3.11 (s,3H), 3.03-3.08 (m, 2H), 2.39 (s, 3H).

Example 432 4-(2-{[2-amino-6-(4-chloro-2-methylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 2 from4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzenesulfonamideand 4-chloro-2-methyl-benzeneboronic acid. LCMS [M+H]⁺ 418; ¹H NMR (400MHz, CD₃OD) δ_(H) ppm 7.81-7.85 (m, 2H), 7.42-7.46 (m, 2H), 7.27-7.28(m, 1H), 7.23 (d, J=1.3 Hz, 2H), 5.78 (s, 1H), 3.63 (br. s., 2H), 2.99(t, J=7.1 Hz, 2H), 2.30 (d, J=0.8 Hz, 3H).

Example 4334-(2-{[2-amino-6-(2-chloro-4-fluorophenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 2 from4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzenesulfonamideand 2-chloro-4-fluoro-benzeneboronic acid. LCMS [M+H]⁺ 422.

Example 4344-(2-{[2-amino-6-(2,3,4-trifluorophenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 2 from4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzenesulfonamideand 2,3,4-trifluorobenzeneboronic acid. LCMS [M+H]⁺ 424.

Example 4354-(2-{[2-amino-6-(4-fluoro-3-methylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 2 from4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzenesulfonamideand 4-fluoro-3-methyl-benzeneboronic acid. LCMS [M+H]⁺ 402; ¹H NMR (400MHz, CD₃OD) δ_(H) ppm 7.80-7.85 (m, 2H), 7.67-7.72 (m, 1H), 7.59-7.65(m, 1H), 7.41-7.46 (m, 2H), 7.07 (dd, J=9.6, 8.6 Hz, 1H), 6.12 (s, 1H),3.64 (t, J=7.2 Hz, 2H), 2.99 (t, J=7.1 Hz, 2H), 2.31 (d, J=2.0 Hz, 3H).

Example 4364-N-cyclopropyl-6-(4-fluoro-2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine and4-fluoro-2,3-dimethyl-benzeneboronic acid. LCMS [M+H]⁺ 273; ¹H NMR (400MHz, CD₃OD) δ_(H) ppm 7.08-7.15 (m, 1H), 6.90-6.98 (m, 1H), 5.90-6.07(m, 1H), 2.53-2.66 (m, 1H), 2.21-2.26 (m, 6H), 0.78 (dd, J=7.1, 2.0 Hz,2H), 0.54 (dd, J=3.7, 1.9 Hz, 2H).

Example 4373-[2-amino-6-(cyclopropylamino)pyrimidin-4-yl]-2-methylbenzonitrile

Prepared according to general procedure 2 from6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine and3-cyano-2-methyl-benzeneboronic acid. LCMS [M+H]⁺ 266; ¹H NMR (400 MHz,CD₃OD) δ_(H) ppm 7.73-7.77 (m, 1H), 7.58-7.63 (m, 1H), 7.42-7.48 (m,1H), 5.91-6.17 (m, 1H), 2.59-2.70 (m, 1H), 2.54 (s, 3H), 0.81 (d, J=4.8Hz, 2H), 0.54-0.59 (m, 2H).

Example 4386-(2,3-dichlorophenyl)-4-N-(prop-2-yn-1-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine and propargyl amine.LCMS [M+H]⁺ 293.

Example 4394-(2-{[2-amino-6-(4-fluoro-2,5-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 9 from4-chloro-6-(4-fluoro-2,5-dimethyl-phenyl)pyrimidin-2-amine and2-(4-sulfamoylphenyl)ethylammonium chloride. LCMS [M+H]⁺ 416.

Example 4404-N-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine and2-(3,5-dimethyl-1H-pyrazol-1-ium-4-yl)ethylammonium dichloride. [M+H]+337; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.34 (s, 1H), 7.21-7.26 (m, 1H),7.18 (dd, J=1.0, 0.5 Hz, 1H), 6.00 (s, 1H), 3.70 (t, J=6.8 Hz, 2H), 2.83(t, J=6.9 Hz, 2H), 2.39 (s, 6H), 2.35 (s, 3H), 2.24 (s, 3H).

Example 4414-N-{2-[(6-chloropyridazin-3-yl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 12 from4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine and3,6-dichloropyridazine. [M+H]+ 370.

Example 442 2-[(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)amino]pyridine-4-carbonitrile

Prepared according to general procedure 12 from4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine and2-chloropyridine-4-carbonitrile. LCMS [M+H]⁺ 360.

Example 4436-[(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)amino]pyridine-3-sulfonamide

Prepared according to general procedure 12 from4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine and6-chloropyridine-3-sulfonamide. LCMS [M+H]⁺ 414.

Example 4441-N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)benzene-1,4-disulfonamide

Prepared according to general procedure 10 from4-N-(4-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine and4-(aminosulfonyl)benzenesulfonyl chloride. LCMS [M+H]⁺ 491; ¹H NMR (400MHz, CD₃OD) δ_(H) ppm 8.04-8.08 (m, 2H), 7.98-8.02 (m, 2H), 7.28 (d,J=7.1 Hz, 1H), 7.16-7.22 (m, 1H), 7.15 (d, J=1.5 Hz, 1H), 5.91 (s, 1H),3.48 (d, J=1.5 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H), 2.34 (s, 3H), 2.22 (s,3H), 1.78 (t, J=6.8 Hz, 2H).

Example 4456-(2,3-dichlorophenyl)-4-N-[2-(4-methanesulfonylphenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from6-chloro-4-N-[2-(4-methylsulfonylphenyl)ethyl]pyrimidine-2,4-diamine and2,3-dichlorobenzene-boronic acid. LCMS [M+H]⁺ 437; ¹H NMR (400 MHz,CD₃OD) δ_(H) ppm 7.90 (d, J=8.6 Hz, 2H), 7.78 (t, J=4.9 Hz, 1H), 7.56(d, J=8.6 Hz, 2H), 7.49 (dd, J=4.9, 0.6 Hz, 2H), 6.08 (s, 1H), 3.84 (s,2H), 3.06-3.11 (m, 5H).

Example 4466-(2,3-dimethylphenyl)-4-N-[1-(1H-pyrazol-1-yl)propan-2-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from4-chloro-6-(2,3-dimethylphenyl)-pyrimidin-2-amine and1-pyrazol-1-ylpropan-2-amine. LCMS [M+H]⁺ 323; ¹H NMR (400 MHz, CDCl₃)δ_(H) ppm 7.71 (d, J=7.8 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.51 (d, J=2.3Hz, 1H), 7.24 (d, J=7.3 Hz, 1H), 7.12 (t, J=7.6 Hz, 1H), 7.04-7.08 (m,1H), 6.30 (t, J=2.3 Hz, 1H), 5.85 (s, 1H), 4.65-4.75 (m, 1H), 4.34-4.41(m, 1H), 4.23 (dd, J=14.1, 6.3 Hz, 1H), 2.29 (s, 3H), 2.18 (s, 3H), 1.16(d, J=6.8 Hz, 3H).

Example 4476-(2,3-dimethylphenyl)-4-N-{2-[(3-methoxyphenyl)amino]ethyl}pyrimidine-2,4-diamine

Prepared according to general procedure 9 from4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine andN′-(3-methoxyphenyl)ethane-1,2-diamine.

LCMS [M+H]⁺ 364; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 7.18-7.26 (m, 1H),7.01-7.07 (m, 1H), 6.96-7.00 (m, 1H), 6.95 (t, J=2.0 Hz, 1H), 6.84 (d,J=7.8 Hz, 1H), 6.76 (dd, J=8.3, 2.0 Hz, 1H), 5.91 (s, 1H), 3.82 (d,J=4.8 Hz, 2H), 3.75 (s, 3H), 3.48 (br. s., 2H), 2.24 (s, 3H), 2.10 (s,3H).

Example 448 6-(2,3-dimethylphenyl)-4-N-{2-[(3-fluoro-4-methylphenyl)amino]ethyl}pyrimidine-2,4-diamine

Step 1: A vial was charged with 2-fluoro-4-iodo-1-methyl-benzene (240mg, 1.0 mmol), ethane-1,2-diamine (0.20 mL, 3.0 mmol), CuCl (9.9 mg,0.10 mmol), and KOH (110 mg, 2.0 mmol). The vial was then flushed withnitrogen and sealed. The mixture was stirred at r.t. for 16 h,thereafter the mixture was extracted with EtOAc. The combined organicphases were dried, concentrated and purified by column chromatography toafford N′-(3-fluoro-4-methyl-phenyl)ethane-1,2-diamine.

Step 2: A mixture of 6-(2,3-dimethylphenyl)-4-chloropyrimidin-2-amine(30 mg, 0.13 mmol), N′-(3-fluoro-4-methyl-phenyl)ethane-1,2-diamine (20mg, 0.12 mmol), and diisopropylethylamine (0.040 mL, 0.23 mmol) in2-propanol (0.50 mL) was heated in a sealed tube at 150° C. for 30 minin a microwave reactor. The reaction mixture was then concentrated andpurified by preparative HPLC. LCMS [M+H]⁺ 366; ¹H NMR (400 MHz, CD₃OD)δ_(H) ppm 7.33-7.37 (m, 1H), 7.21-7.27 (m, 1H), 7.15-7.18 (m, 1H),6.93-6.99 (m, 1H), 6.38-6.45 (m, 2H), 5.99 (s, 1H), 3.72 (s, 2H), 3.39(s, 2H), 2.36 (s, 3H), 2.24 (s, 3H), 2.11 (d, J=1.5 Hz, 3H).

Example 4494-N-{2-[(3,4-dichlorophenyl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine andN′-(3,4-dichlorophenyl)ethane-1,2-diamine. LCMS [M+H]⁺ 402; ¹H NMR (400MHz, CD₃OD) δ_(H) ppm 7.33-7.37 (m, 1H), 7.24 (s, 1H), 7.18 (m, 2H),6.76 (d, J=2.8 Hz, 1H), 6.57 (dd, J=8.8, 2.8 Hz, 1H), 5.97 (s, 3H),3.69-3.73 (m, 2H), 3.37-3.42 (m, 2H), 2.35 (s, 3H), 2.23 (s, 3H).

Example 4504-N-{2-[(5-chloropyridin-2-yl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine andN′-(5-chloro-2-pyridyl)ethane-1,2-diamine. LCMS [M+H]⁺ 369; ¹H NMR (400MHz, CDCl₃) δ_(H) ppm 7.61-7.69 (m, 2H), 7.30 (d, J=7.6 Hz, 1H),7.10-7.22 (m, 3H), 6.17 (br. s., 1H), 3.71 (br. s., 4H), 2.33 (s, 3H),2.24 (s, 3H).

Example 4514-N-{2-[(5-bromopyridin-2-yl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine andN′-(5-bromo-2-pyridyl)ethane-1,2-diamine. LCMS [M+H]⁺ 413; ¹H NMR (400MHz, CD₃OD) δ_(H) ppm 8.07 (dd, J=2.3, 0.8 Hz, 1H), 7.86 (dd, J=9.3, 2.3Hz, 2H), 7.33-7.37 (m, 2H), 7.24 (t, J=7.6 Hz, 1H), 7.15-7.19 (m, 1H),6.90 (dd, J=9.5, 0.6 Hz, 1H), 6.03 (s, 1H), 3.77-3.82 (m, 2H), 3.64-3.69(m, 2H), 2.35 (s, 3H), 2.24 (s, 3H).

Example 4524-[(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)amino]benzene-1-sulfonamide

Prepared according to general procedure 9 from4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine and4-(2-aminoethylamino)benzenesulfonamide. LCMS [M+H]⁺ 413; ¹H NMR (400MHz, CD₃OD) δ_(H) ppm 7.64 (d, J=9.1 Hz, 2H), 7.33-7.37 (m, 1H), 7.24(s, 1H), 7.15-7.19 (m, 1H), 6.70 (d, J=9.1 Hz, 2H), 6.00 (s, 1H),3.72-3.77 (m, 2H), 3.45-3.50 (m, 2H), 2.35 (s, 3H), 2.24 (s, 3H).

Example 4534-N-[2-(4-chlorophenyl)ethyl]-6-(dimethyl-1,2-oxazol-4-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from6-chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine and(3,5-dimethylisoxazol-4-yl)boronic acid. LCMS [M+H]⁺ 344.

Example 4546-(2,3-dimethylphenyl)-4-N-{2-[(pyridin-3-yl)amino]ethyl}pyrimidine-2,4-diamine

Prepared according to general procedure 9 from4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine andN′-(3-pyridyl)ethane-1,2-diamine. LCMS [M+H]⁺ 335; ¹H NMR (400 MHz,CD₃OD) δ_(H) ppm 8.10-8.12 (m, 1H), 7.97-8.00 (m, 1H), 7.72-7.80 (m,2H), 7.34-7.38 (m, 1H), 7.22-7.27 (m, 1H), 7.19 (dd, J=1.0, 0.5 Hz, 1H),6.04 (s, 1H), 3.75-3.80 (m, 2H), 3.54 (t, J=6.2 Hz, 2H), 2.36 (s, 3H),2.25 (s, 3H).

BIOLOGICAL EXAMPLES Biological Example 1 MTH1 Enzymatic Assay and IC50Value Determination

MTH1 catalyzes the hydrolysis of dGTP to dGMP and PPi. By coupling thereaction to pyrophosphatase added in excess PPi is converted to Pi thatcan be detected by using the malachite green assay reagent. Briefly, forIC₅₀ value determination the compound to be analyzed is diluted in assaybuffer in a 1:3 dilution series generating 12 different compoundconcentrations giving a final DMSO concentration of 1% in the assaywell. MTH1 diluted in assay buffer (100 mM Tris-acetate, 40 mM NaCl, 10mM magnesium acetate, 1 mM DTT and 0.005% Tween 20) fortified with E.coli pyrophosphatase (0.8 U/ml) is added to a final concentration of 4.8nM. dGTP diluted in assay buffer is added to a final concentration of100 μM. The reaction mixture is incubated with shaking for 15 minutes at22° C. To 100 μl reaction mixture is 25 μl Malachite green assay regent(0.095% Malachite green in 17% H₂SO₄, 1.5% Ammonium molybdate, 0.17%Tween 20) added followed by incubation with shaking for 15 minutes at22° C. The absorbance of the assay plate is read at 630 nm using anEnVision Multilabel plate reader. The IC₅₀ value is determined byfitting a dose response curve to the data points using nonlinearregression analysis and the equation Y=Bottom+(Top−Bottom)/(1+10̂((LogIC₅₀−X)*HillSlope)), where Y is the read absorbance at 630 nm and X islog [compound].

Using this approach the following representative IC₅₀ values werederived. Examples—4, 6, 11, 18, 31, 32, 35, 36, 40, 43, 44, 46, 51, 52,55, 56, 57, 59, 64, 65, 66, 67, 72, 73, 74, 77, 79, 80, 81, 85, 87, 89,90, 93, 97, 98, 101, 103, 105, 108, 110, 111, 115, 120, 126, 127, 129,131, 132, 135, 141, 142, 144, 146, 148, 149, 151, 159, 164, 165, 168,171, 173, 174, 175, 192, 197, 198, 201, 202, 203, 208, 209, 210, 211,213, 215, 219, 220, 222, 226, 227, 228, 230, 231, 232, 244, 245, 246,249, 252, 254, 256, 257, 259, 260, 264, 266, 267, 269, 273, 275, 276,282, 295, 296, 300, 301, 304, 308, 312, 313, 315, 316, 317, 322, 323,324, 326, 327, 329, 330, 331, 333, 334, 335, 336, 343, 346, 348, 349,350, 351, 359, 361, 363, 367, 374, 376, 379, 381, 386, 389, 391, 397,402, 403, 404, 405, 406, 408, 409, 411, 415, 416, 418, 419, 420, 422,424, 426, 428, 429, 430, 432, 434, 436, 439, 443, 444, 445, 447, 451,453, 454 had IC₅₀'s of less than 200 nM

Examples—3, 8, 9, 10, 17, 22, 24, 25, 42, 45, 54, 60, 95, 96, 102, 113,117, 119, 150, 154, 157, 160, 162, 169, 178, 186, 199, 212, 225, 229,236, 238, 241, 242, 255, 265, 270, 272, 278, 284, 285, 286, 287, 288,290, 291, 292, 293, 294, 298, 302, 306, 318, 319, 320, 339, 340, 347,353, 354, 358, 360, 365, 366, 368, 369, 373, 377, 378, 380, 383, 384,387, 390, 392, 395, 410, 413, 423, 446 had IC₅₀'s of between 200 nM and2 μM

Examples—5, 12, 14, 15, 20, 21, 78, 112, 161, 166, 167, 179, 180, 181,182, 237, 277, 281, 289, 299, 345, 372, 396, 399 had IC₅₀'s of between 2μM and 10 μM

Biological Example 2: MTH1 siRNA Knock Down and Cell Survival

Cells were cultivated in suitable medium supplemented with 10% FBS and10 U/ml PeSt. On day 1, cells were seeded at approximately 30%confluency in 6-well plates in complete medium. The day after, themedium was aspired and fresh medium without antibiotics was added. Thecells were transfected with All-stars Non-targeting RNA (NT RNA, Qiagen)and MTH1 siRNA (5′-CGACGACAGCUACUGGUUU-3′) and Interferin (Polyplus)according to the manufacturer's protocol. On day 5, cells were eithertrypsinized, counted and re-seeded for clonogenic outgrowth on 10-cmplates at 500 cells/plate or washed with PBS and scraped in lysis buffer(10 mM Hepes pH 7.1, 50 mM NaCl, 0.3 M sucrose, 0.1 mM EDTA, 0.5% TritonX100, 1 mM DTT and 1× protease inhib, cocktail (Pierce)) and processedfor Western blot. Blots were stained with anti-MTH1 antibody (rabbitpolyclonal, HPA, KTH, Sweden) and anti-tubulin (mouse monoclonal, SigmaAldrich). After additional 7-10 days, survival plates were fixed/stainedwith 4% methylene blue in MeOH and colonies were counted manually. FIG.1 shows the effect on cell survival following MTH1 siRNA depletion invarious human cancer and normal cell lines.

Biological Example 3: Cell Survival Assay

Cells are cultured in DMEM GlutaMAX™ or other suitable cell medium andplated in cell culture dishes (100 mm×20 mm) (500 cells/dish) andincubated in 5% CO₂ at 37° C. After 5 hours of incubation cells aretreated with compound at various concentrations and left in theincubator for 7-14 days dependent on cell line. Clonogenic survival ismeasured by fixating and staining the cells with methylene blue (4 g/Lin methanol) and number of colonies are counted and compared to vehicletreated dishes. FIG. 2 shows how an MTH1 inhibitor reduces cell survivalin various cancer cell lines, with less effect on normal immortalisedcells (VH10 and BJ hTERT).

Biological Example 4: Cell Viability Assay

Cells are seeded into 96 well plates (1500 cells/well) in DMEM GlutaMAX™or other suitable media dependent on cell line and incubated overnightin 5% CO₂, 37° C. Thereafter cells are treated with compound or vehicleand left in incubator for 3 days until staining with resazurin. Cellsare incubated in resazurin (diluted in suitable media) at 37° C. for 2hours before measuring the fluorescence.

1-28. (canceled)
 29. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein: R¹ representsheteroaryl selected from benzofuran-3-yl, benzothiophen-3-yl,dihydrobenzofuran-7-yl, indol-3-yl, indol-4-yl, indol-5-yl,isoquinolin-4-yl, isoxazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrrol-2-yland quinolin-5-yl, which heteroaryl ring is substituted by one or moresubstituents selected from Y¹, —C₁₋₆alkyl optionally substituted by oneor more Y² and heterocycloalkyl optionally substituted by one or moreY³; or aryl represented by

E¹ represents H, Y^(1a), or —C₁₋₆alkyl optionally substituted by one ormore Y²; E², E³ and E⁴ are selected from H, Y^(1b) and —C₁₋₆alkyloptionally substituted by one or more Y²; and at least one of E², E³ andE⁴ represents Y^(1b) or —C₁₋₆alkyl optionally substituted by one or moreY²; R² represents hydrogen or methyl; R³ represents —C₁₋₁₂alkyloptionally substituted by one or more Z¹ or heterocycloalkyl optionallysubstituted by one or more Z²; or R² and R³ are linked together to form,along with the atoms to which they are attached, a 5- or 6-memberednon-aromatic ring, wherein the link formed by R² and R³ is optionallysubstituted by one or more substituents selected from Z³ and —C₁₋₉alkyloptionally substituted by one or more Z⁴; each Y¹ independentlyrepresents halogen, —CN, —C(O)R^(a), —C(O)N(R^(b))R^(c), —C(O)OR^(d),—N(R^(e))R^(f), —N(R^(g))C(O)R^(h), —N(R^(i))C(O)OR^(j),—N(R^(k))C(O)N(R^(l))R^(m), —NO₂, —N(R^(n))S(O)₂R^(o), —OR^(p),—OC(O)R^(q), —OS(O)₂R^(r), —S(O)_(m)R^(s), —S(O)₂N(R^(t))R^(u),heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³ or heteroaryl optionally substituted byone or more substituents selected from W³; Y^(1a) represents halogen,—CN, —C(O)R^(a), —C(O)N(R^(b))R^(c), —C(O)OR^(d), —N(R^(e))R^(f),—N(R^(g))C(O)R^(h), —N(R^(i))C(O)OR^(j), —N(R^(k))C(O)N(R^(l))R^(m),—NO₂, —N(R^(n))S(O)₂R^(o), —OR^(px), —OC(O)R^(q), —OS(O)₂R^(r),—S(O)_(m)R^(s), —S(O)₂N(R^(t))R^(u), heterocycloalkyl optionallysubstituted by one or more substituents selected from W², aryloptionally substituted by one or more substituents selected from W³ orheteroaryl optionally substituted by one or more substituents selectedfrom W³; Y^(1b) represents halogen, —CN, —C(O)R^(a), —C(O)N(R^(b))R^(c),—C(O)OR^(d), —N(R^(e))R^(f), —N(R^(g))C(O)R^(h), —N(R^(i))C(O)OR^(j),—N(R^(k))C(O)N(R^(l))R^(m), —NO₂, —N(R^(n)(O)₂R^(o), —OR^(p),—OC(O)R^(q), —OS(O)₂R^(r), —S(O)_(m)R^(s), —S(O)₂N(R^(t))R^(u),heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³ or heteroaryl optionally substituted byone or more substituents selected from W³; each R^(a), R^(b), R^(c),R^(d), R^(e), R^(g), R^(h), R^(i), R^(k), R^(l), R^(m), R^(n), R^(p),R^(q), R^(s), R^(t) and R^(u) independently represents hydrogen, —C₁₋₆alkyl optionally substituted by one or more substituents selected fromW¹, heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³, or heteroaryl optionally substituted byone or more substituents selected from W³; or any two R^(b) and R^(c),R^(e) and R^(f), R^(l) and R^(m) and/or R^(t) and R^(u) are linkedtogether to form, along with the nitrogen atom to which they areattached, a 3- to 8-membered monocyclic or bicyclic ring, which ringoptionally contains one or two further heteroatoms and which ringoptionally is substituted by one or more substituents selected from W²,C₁₋₃alkyl optionally substituted by one or more substituents selectedfrom W^(t), and ═O; each R^(f), R^(j), R^(o), R^(r) and R^(px)independently represents C₁₋₆ alkyl optionally substituted by one ormore substituents selected from W¹, heterocycloalkyl optionallysubstituted by one or more substituents selected from W², aryloptionally substituted by one or more substituents selected from W³ orheteroaryl optionally substituted by one or more substituents selectedfrom W³; each Y² independently represents halogen, —CN, —C(O)R^(b1),—C(O)N(R^(c1))R^(d1), —C(O)(OR^(e1), —N(R^(f1))R^(g1),—N(R^(h1))C(O)R^(i1), —N(R_(j1))C(O)OR^(k1), —N(R¹¹)C(O)N(R^(m1))R^(n1),—N(R^(o1))S(O)₂R^(p1), —OR^(q1), —OC(O)R^(r1), —OS(O)₂R^(s1),—S(O)_(m)R^(t1), —S(O)₂N(R^(u1))R^(v1), heterocycloalkyl optionallysubstituted by one or more substituents selected from W¹, aryloptionally substituted by one or more substituents selected from W²,heteroaryl optionally substituted by one or more substituents selectedfrom W², or ═O; each Y³ independently represents halogen, —R^(a1), —CN,—C(O)R^(b1), —C(O)N(R^(c1))R^(d1), —C(O)OR^(e1), —N(R^(f1))R^(g1),—N(R^(h1))C(O)R^(i1), —N(R^(j1))C(O)OR^(k1), —N(R¹¹)C(O)N(R^(m1))R^(n1),—N(R^(o1))S(O)₂R^(p1), —OR^(q1), —OC(O)R^(r1), —OS(O)₂R^(s1),—S(O)_(m)R^(t1), —S(O)₂N(R^(u1))R^(v1), heterocycloalkyl optionallysubstituted by one or more substituents selected from W¹, aryloptionally substituted by one or more substituents selected from W²,heteroaryl optionally substituted by one or more substituents selectedfrom W², or ═O; each R^(a1), R^(b1), R^(c1), R^(d1), R^(e1), R^(f1),R^(h1), R^(i1), R^(j1), R^(l1), R^(m1), R^(n1), R^(o1), R^(q1), R^(r1),R^(t1), R^(u1) and R^(v1) independently represents hydrogen, C₁₋₆ alkyloptionally substituted by one or more substituents selected from W^(t),heterocycloalkyl optionally substituted by one or more substituentsselected from W², aryl optionally substituted by one or moresubstituents selected from W³, or heteroaryl optionally substituted byone or more substituents selected from W³; or any two R^(c1) and R^(d1),R^(f1) and R^(g1), R^(m1) and R^(n1) and/or R^(u1) and R^(v1) are linkedtogether to form, along with the nitrogen atom to which they areattached, a 3- to 8-membered monocyclic or bicyclic ring, which ringoptionally contains one or two heteroatoms and which ring optionally issubstituted by one or more substituents selected from W², C₁₋₃alkyloptionally substituted by one or more substituents selected from W¹, and═O; each R^(g1), R^(k1), R^(p1) and R^(s1) independently represents—C₁₋₆ alkyl optionally substituted by one or more substituents selectedfrom W¹, heterocycloalkyl optionally substituted by one or moresubstituents selected from W², aryl optionally substituted by one ormore substituents selected from W³, or heteroaryl optionally substitutedby one or more substituents selected from W³; each Z¹ independentlyrepresents halogen, —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2),—C(O)OR^(e2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2),—N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2),—N(R^(o2))S(O)₂R^(p2), —OR^(q2), —OC(O)R^(r2), —OS(O)₂R^(s2),—S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionallysubstituted by one or more substituents selected from W⁵, arylrepresented by

or heteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or onesulfur atom and optionally substituted by one or more substituentsselected from W⁶, or ═O; each Z² and Z³ independently representshalogen, —R^(a2), —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2),—N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶; each Z⁴ independentlyrepresents halogen, —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2),—C(O)OR^(e2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2),—N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2),—N(R^(o2))S(O)₂R^(p2), —OR^(q2), —OC(O)R^(r2), —OS(O)₂R^(s2),—S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionallysubstituted by one or more substituents selected from W⁵, aryloptionally substituted by one or more substituents selected from W⁶,heteroaryl optionally substituted by one or more substituents selectedfrom W⁶, or ═O; each R^(a2), R^(b2), R^(c2), R^(d2), R^(e2), R^(f2),R^(h2), R^(i2), R^(j2), R^(l2), R^(m2), R^(n2), R^(o2), R^(q2), R^(r2),R^(t2), R^(u2) and R^(v2) independently represents hydrogen, C₁₋₆ alkyloptionally substituted by one or more substituents selected from W⁴,heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶; or any two R^(c2) and R^(d2),R^(f2) and R^(g2), R^(m2) and R^(n2) and/or R^(u2) and R^(v2) are linkedtogether to form, along with the nitrogen atom to which they areattached, a 3- to 8-membered monocyclic or bicyclic ring, which ringoptionally contains one or two heteroatoms and which ring optionally issubstituted by one or more substituents selected from W⁵, C₁₋₃alkyloptionally substituted by one or more substituents selected from W⁴),and ═O; each R^(g2), R_(k2), R^(p2) and R^(s2) independently representsC₁₋₆ alkyl optionally substituted by one or more substituents selectedfrom W⁴, heterocycloalkyl optionally substituted by one or moresubstituents selected from W⁵, aryl optionally substituted by one ormore substituents selected from W⁶, or heteroaryl optionally substitutedby one or more substituents selected from W⁶; each W¹ and W⁴independently represents halogen, —CN, —N(R^(f3))R^(g3),—N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², heteroaryl optionally substituted by oneor more substituents selected from G², or ═O; each W², W³, W⁵ and W⁶independently represents halogen, —R^(a3), —CN, —C(O)R^(b3),—C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3),—N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², heteroaryl (optionally substituted by oneor more substituents selected from G², or ═O; each W⁷, W⁸, W⁹, W¹⁰ andW¹¹ independently represents hydrogen, halogen, —R^(a3), —CN,—C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3),—N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², or heteroaryl optionally substituted byone or more substituents selected from G²; each R^(a3), R^(b3), R^(c3),R^(d3), R^(e3), R^(f3), R^(h3), R^(i3), R^(j3), R^(l3), R^(m3), R^(n3),R^(o3), R^(r3), R^(t3), R^(u3) and R^(v3) independently representshydrogen or C₁₋₆ alkyl optionally substituted by one or more G³; or anytwo R^(c3) and R^(d3), R^(f3) and R^(g3), R^(m3) and R^(n3) and/orR^(ua) and R^(v3) are linked together to form, along with the nitrogenatom to which they are attached, a 4- to 6-membered ring, which ringoptionally contains one heteroatom and which ring optionally issubstituted by one or more G²; each R^(g3), R^(k3), R^(p3), and R^(s3)independently represents C₁₋₆ alkyl optionally substituted by one ormore G³; each G¹ and G² independently represents halogen, —CN,—C(O)R^(b4), —C(O)N(R^(c4))R^(d4), —C(O)OR^(e4), —N(R^(f4))R^(g4),—N(R^(h4))C(O)R^(i4), —N(R^(j4))C(O)OR^(k4),—N(R^(l4))C(O)N(R^(m4))R^(n4), —N(R^(o4))S(O)₂R^(p4), —OR^(q4),—OC(O)R^(r4), —OS(O)₂R^(s4), —S(O)_(m)R^(t4), —S(O)₂N(R^(u4))R^(v4), or═O; G³ represents halogen, —CN, —C(O)R^(b4), —C(O)N(R^(c4))R^(d4),—C(O)OR^(e4), —N(R^(f4))R^(g4), —N(R^(h4))C(O)R^(i4),—N(R^(j4))C(O)OR^(k4), —N(R¹⁴)C(O)N(R^(m4))R^(n4),—N(R^(o4))S(O)₂R^(p4), —OR^(q4), —OC(O)R^(r4), —OS(O)₂R^(s4),—S(O)_(m)R^(t4), —S(O)₂N(R^(u4))R^(v4), or ═O; each R^(a4), R^(b4),R^(c4), R^(d4), R^(e4), R^(f4), R^(h4), R^(i4), R^(j4), R^(l4), R^(m4),R^(n4), R^(o4), R^(r4), R^(t4), R^(u4) and R^(v4) independentlyrepresents hydrogen or C₁₋₆ alkyl optionally substituted by one or more—F; or any two R^(c4) and R^(d4), R^(f4) and R^(g4), R^(m4) and R^(n4)and/or R^(u4) and R^(v4) are linked together to form, along with thenitrogen atom to which they are attached, a 3- to 6-membered ring, whichring optionally substituted by one or more —F, —CH₃, —CH₂CH₃, —CHF₂,—CF₃, —CH₂CF₃, or ═O; each R^(g4), R^(k4), R^(p4) and R^(s4)independently represent C₁₋₆ alkyl optionally substituted by one or more—F; each m independently represents 0, 1 or 2; provided that thecompound is notN⁴-cyclopropyl-6-(4-methoxy-2-methylphenyl)-2,4-pyrimidinediamine. 30.The compound as claimed in claim 29, wherein: R¹ is represented by

E³ and E⁴ represent hydrogen; and E¹ represents —F and E² represent —F,—Cl, —CH₃ or —CF₃; or E¹ represents —Cl and E² represents —F, —Cl, —CH₃or —CF₃; or E¹ represents —CH₃ and E² represents —F, —Cl, —CH₃, —CF₃,—CN or —N(H)C(O)CH═CH₂; or E² and E⁴ represent hydrogen; and E¹represents —F and E³ represents —F or phenyl; or E¹ represents —Cl andE³ represents —F or —Cl; or E¹ represents —CH₃ and E³ represents —Cl or—OCH₂phenyl; or E¹ represents —OCH₃ and E³ represents —F; or E² and E³represent hydrogen; and E¹ represents —F and E⁴ represents —Cl, —CH₃ or—CN; or E¹ represents —Cl and E⁴ represent —F, —Cl, —CH₃, —CF₃ or —OCH₃;or E¹ represents —CH₃ and E⁴ represent —F, —Cl, —CH₃, —CF₃, —CN,—N(H)C(O)CH═CH₂ or —S(O)₂(4-morpholinyl); or E¹ represents —CF₃ and E⁴represents —F or —CF₃; or E¹ represents —CN and E⁴ represents —Cl; or E¹represents —OCH₃ and E⁴ represents —F, —Cl, Br, —CH₃, —CH(CH₃)₂,—C(CH₃)₃, —CN or —OCH₃; or E¹ and E⁴ represent hydrogen; and E²represents —F and E³ represents —F, —Cl, —OH or —OCH₃; or E² represents—Cl and E³ represents —F or —C(O)(4-morpholinyl); or E² represents —CH₃and E³ represents —F or —OCH₃; or E¹ represents —OCH₃ and E³ represents—OH; or E¹ represents-CH₂OCH₃ and E³ represents (piperidin-4-yl)methoxyor ((1-tertbutoxycarbonyl)piperidin-4-yl)methoxy; or E¹ and E³ representhydrogen; and E² and E⁴ represent —F; or E² and E⁴ represent —CF₃; or E⁴represents hydrogen; and E¹, E² and E³ represent —F; or E¹ and E²represent —Cl and E³ represents —Cl, —OH or —OCH₃; or E¹ and E²represent —CH₃ and E³ represents —F or —OCH₃; or E² and E³ represent —Cland E¹ represents —CH₃; or E² represents hydrogen; and E¹, E³ and E⁴represent —F; or E³ and E⁴ represent —Cl and E¹ represents —CH₃; or E¹and E⁴ represent —Cl and E¹ represents —OCH₃; or E¹ and E⁴ represent—CH₃ and E³ represents —F, —CH₃ or —OCH₃; or E¹ represents —F, E³represents —CH₃ and E⁴ represents —Cl; or E¹ represents —Cl, E³represents —F and E⁴ represents —CH₃; or E¹ represents —Cl, E³represents —CH₃ and E⁴ represents —F; or E¹ and E⁴ represent —CH₃ and E³represents —F; or E¹ represents —CH₃, E⁴ represents —Cl and E³represents —CF₃ or —OCH₃; or E¹ represents hydrogen; and E² and E⁴represent —CH₃ and E³ represents —OH; or E³ represents hydrogen; and E¹and E² represent —Cl and E⁴ represents —CH₃.
 31. The compound as claimedin claim 30, wherein: E³ and E⁴ represent hydrogen; and E¹ represents —Fand E² represents —F, —Cl, or —CF₃; or E¹ represents —Cl and E²represents —Cl, —CH₃ or —CF₃; or E¹ represents —CH₃ and E² represents—Cl, —CH₃, —CN or —N(H)C(O)CH═CH₂; or E² and E⁴ represent hydrogen; andE¹ and E³ represent —F; or E¹ represents —Cl and E³ represents —F or—Cl; or E¹ represents —CH₃ and E³ represents —Cl; or E² and E³ representhydrogen; and E¹ represents —F and E⁴ represents —Cl, —CH₃ or —CN; or E¹represents —Cl and E⁴ represents —F, —Cl, —CH₃ or —CF₃; or E¹ represents—CH₃ and E⁴ represent, —Cl, —CH₃, —CF₃, —CN or —N(H)C(O)CH═CH; or E¹represents —CF₃ and E⁴ represents —F or —CF₃; or E¹ represents —CN andE⁴ represents —Cl; or E⁴ represents hydrogen; and E¹, E² and E³represent —F; or E¹ and E² represent —CH₃ and E³ represents —F₃; or E²and E³ represent —Cl and E¹ represents —CH₃; or E² represents hydrogen;and E¹, E³ and E⁴ represent —F; or E³ and E⁴ represent —Cl and E¹represents —CH₃; or E¹ and E⁴ represent —CH₃ and E³ represents —F or—CH₃; or E¹ represents —F, E³ represents —CH₃ and E⁴ represents —Cl; orE¹ represents —Cl, E³ represents —F and E⁴ represents —CH₃; or E¹represents —Cl, E³ represents —CH₃ and E⁴ represents —F; or E¹ and E⁴represent —CH₃ and E³ represents —F; or E¹ represents —CH₃, E³represents —CF₃ and E⁴ represents —Cl; or E¹ represents hydrogen; and E²and E⁴ represent —CH₃ and E³ represents —OH; or E³ represents hydrogen;and E¹ and E² represent —Cl and E⁴ represents —CH₃.
 32. (canceled) 33.The compound as claimed in claim 29, wherein: R² represents hydrogen ormethyl.
 34. The compound as claimed in claim 29, wherein: R³ represents—C₁₋₆alkyl optionally substituted by Z¹.
 35. The compound as claimed inclaim 29, wherein: R³ represents —C₂₋₆alkyl optionally substituted by Z¹or heterocycloalkyl optionally substituted by Z².
 36. The compound asclaimed in claim 29, wherein: R³ represents —C₁₋₂alkyl optionallysubstituted with one or more —F.
 37. The compound as claimed in anyclaim 29, wherein: R³ represents


38. The compound as claimed in claim 29, wherein: R³ represents—C₁₋₆alkyl substituted by heteroaryl having 1 to 3 nitrogen atoms, oneoxygen atom and/or one sulfur atom and which heteroaryl is optionallysubstituted by one or more substituents selected from W³.
 39. Thecompound as claimed in claim 29, wherein: R³ represents —C₃₋₆alkyl or aheterocycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclopropylethyl, cyclobutylethyl, cyclopropylpropyl, oxetanyl,tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl or morpholinyl wherein the C₃₋₆alkyl isoptionally substituted by Z¹ and the heterocycloalkyl is optionallysubstituted by Z².
 40. The compound as claimed in claim 34, wherein: Z¹represents —F, —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2),—N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionallysubstituted by one or more substituents selected from W⁵, arylrepresented by

or heteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or onesulfur atom and optionally substituted by one or more substituentsselected from W⁶.
 41. The compound as claimed in claim 40 wherein: Z¹represents —F, —CN, —C(O)NH₂, —C(O)N(R^(c2))R^(d2),—C(O)-(4-morpholinyl), —C(O)OEt, —N(H)C(O)Me, —N(H)C(O)R^(i2),—N(H)C(O)CH₂NMe₂, —N(H)C(O)OCMe₃, —N(H)C(O)OCH₂Ph, —N(Me)C(O)OCMe₃,—N(H)C(O)N(H)Me, —N(H)C(O)N(H)CHMe₂, —N(H)S(O)₂Me, —OMe, —OCF₃, —OEt, orheterocycloalkyl selected from dihydropyridinyl, imidazolinyl,morpholinyl, oxanyl, piperazinyl, piperidinyl, pyrrolidinyl andquinuclidinyl, wherein the heterocycloalkyl is optionally substituted byone or more substituents selected from W⁵.
 42. The compound as claimedin claim 40 wherein: each W⁷, W¹⁰ and W¹¹ independently representshydrogen, halogen, —R^(a3) or —CN; and one of W⁸ and W⁹ representshydrogen, halogen, —R^(a3) or —CN and the other represents halogen,—R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3),—N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3),—N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x),—OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3),heterocycloalkyl optionally substituted by one or more substituentsselected from G¹, aryl optionally substituted by one or moresubstituents selected from G², or heteroaryl optionally substituted byone or more substituents selected from G².
 43. The compound as claimedin claim 29, wherein: R² and R³ are linked together to form, along withthe atoms to which they are attached, a 5- to 6-membered non-aromaticring, wherein the link formed by R² and R³ is optionally substituted byone or more substituents selected from Z³ or —C₁₋₉alkyl optionallysubstituted by one or more Z⁴.
 44. The compound as claimed in claim 43,wherein: Z³ is not present or is selected from —F, —R^(a2),—C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2),—N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2),—N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2),heterocycloalkyl optionally substituted by one or more substituentsselected from W⁵, aryl optionally substituted by one or moresubstituents selected from W⁶, or heteroaryl optionally substituted byone or more substituents selected from W⁶; and/or Z⁴ is not present oris selected from —F, —C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2),—N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2),—N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2),—S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionallysubstituted by one or more substituents selected from W⁵, aryloptionally substituted by one or more substituents selected from W⁶, orheteroaryl optionally substituted by one or more substituents selectedfrom W⁶.
 45. A pharmaceutical formulation comprising a compound asclaimed in claim 29, or a pharmaceutically acceptable salt thereof, inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier. 46-47. (canceled)
 48. A method of treatment of a diseaseselected from Soft Tissue Cancers selected from sarcoma, myxoma,rhabdomyoma, fibroma, lipoma and teratoma; Lung cancers/diseasesselected from bronchogenic carcinoma, alveolar carcinoma, bronchialadenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal cancers/diseases selected from cancers of theesophagus, stomach, pancreas, small bowel, and large bowel;Genitourinary tract cancers/diseases selected from cancers of thekidney, bladder and urethra, prostate, and testis; Livercancers/diseases selected from hepatoma, cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bonecancers/diseases selected from osteogenic sarcoma, fibrosarcoma,malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma,malignant lymphoma, multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma, benign chondroma, chondroblastoma,chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervoussystem cancers/diseases selected from cancer of the skull, meningesbrain, and the spinal cord; Gynecological cancers/diseases selected fromcancers of the uterus, cervix, ovaries, vulva, vagina, fallopian tubes;Hematologic cancers; Skin cancers/diseases selected from malignantmelanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi'ssarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma,keloids; Adrenal glands cancers/diseases, neuroblastoma,neurofibromatosis and head and neck cancers, and breast cancer; whichmethod comprises administration of a therapeutically effective amount acompound as claimed in claim 29, or a pharmaceutically acceptable saltthereof, to a patient in need of such treatment.
 49. The method asclaimed in claim 48, wherein the cancer is selected from the groupconsisting of breast cancers, prostate cancers, lung cancers,oesophageal cancers, colon cancers, brain cancers, skin cancers, ovariancancers, testicular cancers, neurofibromatosis and leukemias. 50.(canceled)
 51. A combination product comprising: (A) a compound asclaimed in claim 29, or a pharmaceutically acceptable salt thereof; and(B) one or more other therapeutic agent(s) that is/are useful in thetreatment of a disease, wherein each one of components (A) and (B) isformulated in admixture with a pharmaceutically-acceptable adjuvant,diluent or carrier, and wherein the disease is selected from: SoftTissue Cancers selected from sarcoma, myxoma, rhabdomyoma, fibroma,lipoma and teratoma; Lung cancers/diseases selected from bronchogeniccarcinoma, alveolar carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma; Gastrointestinal cancers/diseasesselected from cancers of the esophagus, stomach, pancreas, small bowel,and large bowel; Genitourinary tract cancers/diseases selected fromcancers of the kidney, bladder and urethra, prostate, and testis; Livercancers/diseases selected from hepatoma, cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bonecancers/diseases selected from osteogenic sarcoma, fibrosarcoma,malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma,malignant lymphoma, multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma, benign chondroma, chondroblastoma,chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervoussystem cancers/diseases selected from cancer of the skull, meningesbrain, and the spinal cord; Gynecological cancers/diseases selected fromcancers of the uterus, cervix, ovaries, vulva, vagina, fallopian tubes;Hematologic cancers; Skin cancers/diseases selected from malignantmelanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi'ssarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma,keloids; Adrenal glands cancers/diseases, neuroblastoma,neurofibromatosis and head and neck cancers, and breast cancer.
 52. Thecombination product as claimed in claim 51, wherein component (B) isselected from the group consisting of anti-microtubule agents, platinumcoordination complexes, alkylating agents, antibiotic agents,topoisomerase II inhibitors, antimetabolites, topoisomerase Iinhibitors, hormones and hormonal analogues, signal transduction pathwayinhibitors; kinase inhibitors; angiogenesis inhibitors;immunotherapeutic agents; pro-apoptotic agents; and cell cycle signalinginhibitors. 53-54. (canceled)
 55. The compound as claimed in claim 30,wherein: R³ represents —C₁₋₆alkyl optionally substituted by Z¹.
 56. Thecompound as claimed in claim 30, wherein: R³ represents —C₁₋₂alkyloptionally substituted with one or more —F.
 57. The compound as claimedin claim 55, wherein: E³ and E⁴ represent hydrogen; and E¹ represents —Fand E² represent —F, —Cl, —CH₃ or —CF₃; or E¹ represents —Cl and E²represents —F, —Cl, —CH₃ or —CF₃; or E¹ represents —CH₃ and E²represents —F, —Cl, —CH₃, —CF₃, —CN or —N(H)C(O)CH═CH₂.
 58. The compoundas claimed in claim 56, wherein: R³ represents —C₁₋₂alkyl optionallysubstituted with one or more —F.
 59. The compound as claimed in claim29, selected from4-N-cyclopropyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine,4-[2-amino-6-(methylamino)pyrimidin-4-yl]-2,3-dichlorophenol, methyl(2E)-3-{3-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}prop-2-enoate,6-(2,3-dimethylphenyl)-4-N-(2-phenylethyl)pyrimidine-2,4-diamine,6-(3-chloro-2-methoxypyridin-4-yl)-4-N-methylpyrimidine-2,4-diamine,4-(2,3-dimethylphenyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-2-amine,4-(2,3-dichlorophenyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-2-amine,4-[1-(benzenesulfonyl)-1H-indol-3-yl]-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-2-amine,6-(2,3-dimethylphenyl)-4-N-[2-(4-methoxyphenyl)ethyl]pyrimidine-2,4-diamine,6-(2,3-dimethylphenyl)-4-N-[2-(2-methoxyphenyl)ethyl]pyrimidine-2,4-diamine,6-(2,3-dimethylphenyl)-4-N-[2-(4-methylphenyl)ethyl]pyrimidine-2,4-diamine,4-N-[2-(4-chlorophenyl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine,6-(2,3-dimethylphenyl)-4-N-(3-phenylpropyl)pyrimidine-2,4-diamine,6-(2,3-dimethylphenyl)-4-N-[2-(phenylamino)ethyl]pyrimidine-2,4-diamine,6-(2,3-dimethylphenyl)-4-N-[2-(1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine,6-(2,3-dimethylphenyl)-4-N-pentylpyrimidine-2,4-diamine,4-[2-amino-6-(methylamino)pyrimidin-4-yl]-2,6-dimethylphenol,4-[2-amino-6-(methylamino)pyrimidin-4-yl]-2-methoxyphenol,4-[2-amino-6-(methylamino)pyrimidin-4-yl]-2-fluorophenol,4-N-methyl-6-(2-methylphenyl)pyrimidine-2,4-diamine,6-[1-(4-chlorobenzenesulfonyl)-1H-indol-3-yl]-4-N-methylpyrimidine-2,4-diamine,4-N-methyl-6-(4-methyl-1H-indazol-5-yl)pyrimidine-2,4-diamine,4-N-methyl-6-(3-methylphenyl)pyrimidine-2,4-diamine,6-(1H-indol-5-yl)-4-N-methylpyrimidine-2,4-diamine,6-(3-chloropyridin-4-yl)-4-N-methylpyrimidine-2,4-diamine,4-N-cyclobutyl-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine,4-N-cyclopentyl-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine,6-(1-benzofuran-3-yl)-4-N-methylpyrimidine-2,4-diamine,6-(1-benzothiophen-3-yl)-4-N-methylpyrimidine-2,4-diamine,6-(5-bromo-2-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine,6-[4-(benzyloxy)-2-methylphenyl]-4-N-methylpyrimidine-2,4-diamine,6-(4-methoxy-2,5-dimethylphenyl)-4-N-methylpyrimidine-2,4-diamine,6-(4,5-dichloro-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine,6-(2,5-dichloro-4-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine,6-(4-fluoro-2,5-dimethylphenyl)-4-N-methylpyrimidine-2,4-diamine,6-[5-chloro-2-methyl-4-(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine,6-(5-tert-butyl-2-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine,6-(2-fluoro-5-methylphenyl)-4-N-methylpyrimidine-2,4-diamine,6-(5-chloro-2-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine,6-(5-fluoro-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine,6-(2-chloro-5-fluorophenyl)-4-N-methylpyrimidine-2,4-diamine,6-[5-fluoro-2-(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine,6-(2,5-dichlorophenyl)-4-N-methylpyrimidine-2,4-diamine,6-(5-chloro-2-fluoro-4-methylphenyl)-4-N-methylpyrimidine-2,4-diamine,6-(5-chloro-2-methylphenyl)-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine,4-N-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-2,5-dimethylphenyl)pyrimidine-2,4-diamine,4-N-[2-(4-chlorophenyl)ethyl]-6-(2,5-dimethylphenyl)pyrimidine-2,4-diamine,6-(2-chloro-3-methylphenyl)-4-N-methylpyrimidine-2,4-diamine,6-(2-chloro-3-methylphenyl)-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine,4-N-[2-(4-chlorophenyl)ethyl]-6-(1H-indol-4-yl)pyrimidine-2,4-diamine,6-[5-fluoro-2-(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine,6-(2,5-dichlorophenyl)-4-N-methylpyrimidine-2,4-diamine,4-N-cyclopropyl-6-(1H-indol-5-yl)pyrimidine-2,4-diamine, tert-Butyl(3-((2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl)amino)-2,2-dimethyl-propyl)carbamate,6-(5-chloro-4-methoxy-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine,4-N-{bicyclo[2,2,1]heptan-2-yl}-6-(3-chloro-2-methylphenyl)pyrimidine-2,4-diamine,6-(3-chloro-2-methylphenyl)-4-N-ethylpyrimidine-2,4-diamine,4-N-[2-(2-chlorophenoxy)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine,6-(2,3-dimethylphenyl)-4-N-[2-(pyridin-3-yloxy)propyl]pyrimidine-2,4-diamine,6-(2,3-dimethylphenyl)-4-N-(1H-indazol-5-ylmethyl)pyrimidine-2,4-diamine,3-[2-amino-6-(methylamino)pyrimidin-4-yl]-2-methylbenzonitrile,6-(4-fluoro-2,3-dimethylphenyl)-4-N-methylpyrimidine-2,4-diamine,6-(2,3-dihydro-1-benzofuran-7-yl)-4-N-methylpyrimidine-2,4-diamine,4-N-methyl-6-[2-methyl-5-(morpholine-4-sulfonyl)phenyl]pyrimidine-2,4-diamine,6-(2,3-dimethylphenyl)-4-N-[2-(pyridin-3-yl)ethyl]pyrimidine-2,4-diamine,benzylN-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-carbamate,tert-butyl4-({[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}methyl)piperidine-1-carboxylate,N-{3-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}-3-hydroxypyridine-2-carboxamide,N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}prop-2-enamide,(2E)-N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-4-(dimethylamino)but-2-enamide,N-{3-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}ethene-1-sulfonamide,N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}prop-2-ynamide,N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-2-oxopropanamide,6-(2,3-Dimethylphenyl)-4-N-[2-(5-methyl-1H-1,2,4-triazol-3-yl)ethyl]pyrimidine-2,4-diamine,4-N-{[4-(Dimethylamino)phenyl]methyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine,6-(2,3-Dimethylphenyl)-4-N-{[1-(pyrimidin-2-yl)piperidin-3-yl]methyl}pyrimidine-2,4-diamine,6-(2,3-Dimethylphenyl)-4-N-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]pyrimidine-2,4-diamine,6-(2,3-Dimethylphenyl)-4-N-{[1-(pyridin-2-yl)piperidin-3-yl]methyl}pyrimidine-2,4-diamine,6-(2,3-Dimethylphenyl)-4-N-[(2-phenyl-2H-1,2,3-triazol-4-yl)methyl]pyrimidine-2,4-diamine,tert-ButylN-(4-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}butyl)-carbamate,tert-ButylN-(5-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}pentyl)-carbamate,6-(2,3-Dimethylphenyl)-4-N-(prop-2-en-1-yl)pyrimidine-2,4-diamine,6-(2,3-dichlorophenyl)-4-N-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]pyrimidine-2,4-diamine6-(3-chloro-2-methylphenyl)-4-N-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]pyrimidine-2,4-diamine4-N-Cyclopropyl-6-(2,3,4-trichlorophenyl)pyrimidine-2,4-diamine,6-(2,3-dimethylphenyl)-4-N—(²H₃)methylpyrimidine-2,4-diamine,6-(2-chloro-3-methylphenyl)-4-N—(²H₃)methylpyrimidine-2,4-diamine, and3-[2-amino-6-(cyclopropylamino)pyrimidin-4-yl]-2-methylbenzonitrile, ora pharmaceutically acceptable salt thereof.